Thiazolopyrimidinones and methods of use thereof

ABSTRACT

The present invention relates to certain thiazolopyrimidinone compounds, pharmaceutical compositions comprising such compounds, and methods of treatment using such compounds.

RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.15/094,687, filed Apr. 8, 2016, which is a continuation of InternationalApplication No. PCT/EP2014/071522, filed Oct. 8, 2014 claiming priorityto International Application No. PCT/CN2013/085031, filed Oct. 11, 2013and International Application No. PCT/CN2014/085959, filed Sep. 5, 2014,each of which are incorporated herein by reference in its entirety.

FIELD OF INVENTION

The present invention relates to certain thiazolopyrimidinone compounds,pharmaceutical compositions comprising such compounds, and methods oftreating neurological and psychiatric conditions, and other diseases andmedical conditions, with such compounds and pharmaceutical compositions.The present invention also relates to certain thiazolopyrimidinonecompounds for use in modulating NMDA receptor activity.

BACKGROUND OF THE INVENTION

N-Methyl-D-aspartate (NMDA) receptors play an important role in variouscentral nervous system functions, such as synaptic transmission andsynaptic plasticity, and underlying functions such as regulation oflong-term potentiation, long-term depression, and experience, dependentsynaptic refinement. Costa et al., “A Novel Family of Negative andPositive Allosteric Modulators of NMDA Receptors,” J. Pharmacol. Exp.Ther. 2010, 335, 614-621, at 614. Excitatory nerve transmission in thesereceptors is regulated by the neurotransmitter, L-glutamate, and theagonist, NMDA. PCT Intl. Publ. No. WO2007/006175, paras. 2-3. NMDAreceptors are ligand-gated ion channels comprising seven subunits:GluN1, GluN2A-D, and GluN3A-B. Costa at 615. The NR2A and NR2B subunitshave been implicated in glutamate binding to the receptor, while the NR1subunit may play a role in the binding of the receptor co-agonist,glycine. The three-dimensional structures of the glutamate- andglycine-binding pockets of NMDA receptors have been characterized,allowing for design of more subtype-specific modulators.

Modulation of these receptors effects changes in learning and memory,and modulators of NMDA receptor activity are considered as potentialtreatments for neurological and psychiatric conditions including pain,neuropathic pain, inflammatory pain, peripheral neuropathy, stroke,epilepsy, neurodegeneration, schizophrenia, drug addiction, mooddisorders, post-traumatic stress disorder, seizures, convulsions,age-associated memory impairment, and depression. Costa at 614.Modulation of NMDA receptor activity is linked with a neuroprotectiverole, with applications in treatments for stroke, traumatic braininjury, ischemia, and neurodegenerative diseases such as Alzheimer'sdisease, Parkinson's disease, Huntington's disease, amyotrophic lateralsclerosis, and Creutzfeldt-Jakob disease. Costa at 614-615.

There is a particular need for NMDA receptor modulators that demonstratesubtype selectivity among members of the NMDA receptor family. Selectiveagents will allow for optimal therapeutic activity with a reducedpotential for adverse side effects. Costa at 615.

There remains a need for potent NMDA receptor modulators with desirablepharmaceutical properties. Certain thiazolopyrimidinone derivatives havebeen found in the context of this invention to have NMDAreceptor-modulating activity.

SUMMARY OF THE INVENTION

In one aspect, the invention is directed to a compound of Formula II:

wherein

-   R^(a) is C₁₋₆alkyl or C₂₋₆alkenyl, each optionally substituted with    one or more R^(b) substituents; C₂₋₆alkynyl; halo; —C(O)R^(c);    —NR^(d)R^(e); —C(O)NR^(d)R^(e); —C(S)NR^(d)R^(e);    —C(═N—OH)—C₁₋₄alkyl; —OC₁₋₄alkyl; —OC₁₋₄haloalkyl; —SC₁₋₄alkyl;    —SO₂C₁₋₄alkyl; cyano; C₃₋₆cycloalkyl optionally substituted with one    or more R^(f) substituents; or a phenyl, monocyclic heteroaryl, or    heterocycloalkyl ring, each ring optionally substituted with one or    more R^(g) substituents;    -   wherein each R^(b) substituent is independently selected from        the group consisting of —OH, —C₁₋₄alkoxy, —NR^(d)R^(e),        —C(O)NR^(d)R^(e), —SC₁₋₄alkyl, —SO₂C₁₋₄alkyl, cyano, halo,        C₃₋₆cycloalkyl, and monocyclic heteroaryl;    -   R^(c) is C₁₋₄alkyl, —C₁₋₄haloalkyl, C₃₋₆cycloalkyl, or a        monocyclic, carbon-linked heterocycloalkyl;    -   R^(d) is H or C₁₋₄alkyl;    -   R^(e) is H; C₁₋₄alkyl optionally substituted with —CN, —CF₃,        —OH, or a monocyclic heterocycloalkyl; C₃₋₆cycloalkyl; —OH; or        —OC₁₋₄alkoxy;    -   or R^(d) and R^(e) taken together with the nitrogen to which        they are attached form a heterocycloalkyl, optionally        substituted with C₁₋₄alkyl or —OH;    -   each R^(f) substituent is independently selected from the group        consisting of: C₁₋₄alkyl optionally substituted with —OH, cyano,        or C₁₋₄alkoxy; —OH; halo; C₁₋₄haloalkyl; —CONH₂; and cyano; and    -   each R^(g) substituent is independently selected from the group        consisting of C₁₋₄alkyl, —CF₃, halo, —NH₂, —OCH₃, cyano, and        —OH;-   R¹ is selected from the group consisting of H, C₁₋₆alkyl,    C₁₋₄haloalkyl, C₃₋₆cycloalkyl, halo, —OC₁₋₄alkyl, —OC₁₋₄haloalkyl,    cyano, and —C(O)C₁₋₄alkyl; or R^(a) and R¹ taken together with the    carbons to which they are attached form a 5- to 7-membered ring,    optionally containing an O or NH, and optionally substituted with    one or more R^(h) substituents;    -   wherein each R^(h) substituent is independently        —C(O)NR^(i)R^(j), cyano, or is C₁₋₄alkyl optionally substituted        with —OH, —OCH₃, cyano, or —C(O)NR^(i)R^(j); or two R^(h) groups        attached to the same carbon and taken together with the carbon        to which they are attached form a carbonyl or a C₃₋₆cycloalkyl;        -   wherein R^(i) and R^(j) are each independently H or            C₁₋₄alkyl;-   R² is —R^(m), —OR^(m), or —NR^(m)R^(n);    -   wherein R^(m) is aryl or heteroaryl, each optionally substituted        with one or more R^(s) substituents;        -   wherein each R^(s) substituent is independently selected            from the group consisting of C₁₋₄alkyl, C₂₋₄alkenyl            (optionally substituted with halo), C₂₋₄alkynyl,            C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄alkyl-OH, C₁₋₄haloalkoxy,            halo, cyano, C₃₋₆cycloalkyl (optionally substituted with —OH            or halo), monocyclic heteroaryl, —NH₂, —NO₂,            —NHSO₂C₁₋₄alkyl, and —SO₂C₁₋₄alkyl;    -   R^(n) is H, C₁₋₄haloalkyl, or C₁₋₄alkyl optionally substituted        with —OH or C₁₋₄alkoxy;        -   or R^(m) and R^(n) taken together with the nitrogen to which            they are attached form a pyrrolidine or piperidine ring,            optionally substituted with C₁₋₄alkyl and optionally fused            to phenyl, wherein said phenyl is optionally substituted            with halo;-   R³ is H or methyl; and-   R⁴ is H or fluoro;-   or a pharmaceutically acceptable salt thereof.

In one aspect, the invention is directed to a compound of Formula I:

wherein

-   R^(a) is C₁₋₆alkyl optionally substituted with one or more R^(b)    substituents; C₂₋₆alkenyl; C₂₋₆alkynyl; halo; —C(O)R^(c);    —NR^(d)R^(e); —C(O)NR^(d)R^(e); —C(S)NR^(d)R^(e);    —C(═N—OH)—C₁₋₄alkyl; —SO₂C₁₋₄alkyl; cyano; C₃₋₆cycloalkyl optionally    substituted with one or more R^(f) substituents; or a phenyl,    monocyclic heteroaryl, or heterocycloalkyl ring, each ring    optionally substituted with one or more R^(g) substituents;    -   wherein each R^(b) substituent is independently selected from        the group consisting of —OH, —C₁₋₄alkoxy, —NR^(d)R^(e),        —C(O)NR^(d)R^(e), —SC₁₋₄alkyl, —SO₂C₁₋₄alkyl, cyano, halo, and        monocyclic heteroaryl;    -   R^(c) is C₁₋₄alkyl, —C₁₋₄haloalkyl, C₃₋₆cycloalkyl, or a        monocyclic, carbon-linked heterocycloalkyl;    -   R^(d) is H or C₁₋₄alkyl;    -   R^(e) is H; C₁₋₄alkyl optionally substituted with —CN, —CF₃,        —OH, or a monocyclic heterocycloalkyl; C₃₋₆cycloalkyl; —OH; or        —OC₁₋₄alkoxy;    -   or R^(d) and R^(e) taken together with the nitrogen to which        they are attached form a heterocycloalkyl, optionally        substituted with C₁₋₄alkyl or —OH;    -   each R^(f) substituent is independently selected from the group        consisting of: C₁₋₄alkyl optionally substituted with —OH, cyano,        or C₁₋₄alkoxy; C₁₋₄haloalkyl; —CONH₂; and cyano; and    -   each R^(g) substituent is independently selected from the group        consisting of C₁₋₄alkyl, —CF₃, halo, —NH₂, —OCH₃, cyano, and        —OH;-   R¹ is selected from the group consisting of H, C₁₋₆alkyl,    C₁₋₄haloalkyl, and C₃₋₆cycloalkyl; or R^(a) and R¹ taken together    with the carbons to which they are attached form a 5- to 7-membered    ring, optionally containing an O or NH, and optionally substituted    with one or more R^(h) substituents;    -   wherein each R^(h) substituent is independently        —C(O)NR^(i)R^(j), cyano, or is C₁₋₄alkyl optionally substituted        with —OH, —OCH₃, cyano, or —C(O)NR^(i)R^(j); or two R^(h) groups        attached to the same carbon and taken together with the carbon        to which they are attached form a carbonyl or a C₃₋₆cycloalkyl;        -   wherein R^(i) and R^(j) are each independently H or            C₁₋₄alkyl;-   R² is —R^(m), —OR^(m), or —NR^(m)R^(n);    -   wherein R^(m) is aryl or heteroaryl, each optionally substituted        with one or more R^(s) substituents;        -   wherein each R^(s) substituent is independently selected            from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl,            C₁₋₄alkoxy, C₁₋₄alkyl-OH, C₁₋₄haloalkoxy, halo, cyano,            C₃₋₆cycloalkyl, —NHSO₂C₁₋₄alkyl, and —SO₂C₁₋₄alkyl;    -   R^(n) is H, C₁₋₄haloalkyl, or C₁₋₄alkyl optionally substituted        with —OH or C₁₋₄alkoxy;        -   or R^(m) and R^(n) taken together with the nitrogen to which            they are attached form a pyrrolidine or piperidine ring,            optionally substituted with C₁₋₄alkyl and optionally fused            to phenyl, wherein said phenyl is optionally substituted            with halo;-   R³ is H or methyl; and-   R⁴ is H or fluoro;-   or a pharmaceutically acceptable salt thereof.

In a further aspect, the invention relates to pharmaceuticalcompositions each comprising an effective amount of at least onecompound of Formula I or II or a pharmaceutically acceptable salt of acompound of Formula I or II. Pharmaceutical compositions according tothe invention may further comprise at least one pharmaceuticallyacceptable excipient.

In another aspect, the invention is directed to a method of treating asubject suffering from a disease or medical condition mediated by NMDAreceptor activity, comprising administering to the subject in need ofsuch treatment an effective amount of at least one compound of Formula Ior II or a pharmaceutically acceptable salt of a compound of Formula Ior II, or comprising administering to the subject in need of suchtreatment an effective amount of a pharmaceutical composition comprisingan effective amount of at least one compound of Formula I or II or apharmaceutically acceptable salt of a compound of Formula I or II.

An aspect of the present invention concerns the use of compound ofFormula I or II, or a pharmaceutically acceptable salt thereof, for thepreparation of a medicament used in the treatment, prevention,inhibition, or elimination of a disease or medical condition mediated byNMDA receptor activity.

An aspect of the present invention concerns the use of a compound ofFormula I or II, or a pharmaceutically acceptable salt thereof, for thepreparation of a medicament used in the treatment, prevention,inhibition or elimination of a disease or medical condition mediated byNMDA receptor activity.

In another aspect, the compounds of Formula I or II, andpharmaceutically acceptable salts thereof, are useful as NMDA receptormodulators. Thus, the invention is directed to a method for modulatingNMDA receptor activity, including when the NMDA receptor is in asubject, comprising exposing the NMDA receptor to an effective amount ofat least one compound of Formula I or II, or a pharmaceuticallyacceptable salt of a compound of Formula I or II.

In yet another aspect, the present invention is directed to methods ofmaking compounds of Formula I or II, and pharmaceutically acceptablesalts thereof.

In certain embodiments of the compounds, pharmaceutical compositions,and methods of the invention, the compound of Formula I or II is acompound selected from those species described or exemplified in thedetailed description below, or is a pharmaceutically acceptable salt ofsuch a compound.

Additional embodiments, features, and advantages of the invention willbe apparent from the following detailed description and through practiceof the invention.

DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS

For the sake of brevity, the disclosures of the publications cited inthis specification, including patents and patent applications, areherein incorporated by reference in their entirety.

Most chemical names were generated using IUPAC nomenclature herein. Somechemical names were generated using different nomenclatures oralternative or commercial names known in the art. In the case ofconflict between names and structures, the structures prevail.

General Definitions

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings. If a definition is missing, the conventional definition asknown to one skilled in the art controls. If a definition providedherein conflicts or is different from a definition provided in any citedpublication, the definition provided herein controls.

As used herein, the terms “including,” “containing,” and “comprising”are used in their open, non-limiting sense.

As used herein, the singular forms “a,” “an,” and “the” include pluralreferents unless the context clearly dictates otherwise.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about.” It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity that could be obtained under the particular stoichiometricconditions. Concentrations that are given as percentages refer to massratios, unless indicated differently.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, the preferredmethods and materials are now described. All publications mentionedherein are incorporated herein by reference to disclose and describe themethods and/or materials in connection with which the publications arecited.

Except as otherwise noted, the methods and techniques of the presentembodiments are generally performed according to conventional methodswell known in the art and as described in various general and morespecific references that are cited and discussed throughout the presentspecification. See, e.g., Loudon, Organic Chemistry, 4^(th) edition, NewYork: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith andMarch, March's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, 5^(th) edition, Wiley-Interscience, 2001.

Chemical Definitions

As used herein, “alkyl” refers to a saturated, straight- orbranched-chain hydrocarbon group having from 1 to 10 carbon atoms.Representative alkyl groups include, but are not limited to, methyl,ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl,2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl,neopentyl, n-hexyl, and the like, and longer alkyl groups, such asheptyl, octyl, and the like. As used herein, “lower alkyl” means analkyl having from 1 to 6 carbon atoms.

The term “alkenyl” refers to straight chain or branched hydrocarbylgroups having from 2 to 6 carbon atoms and preferably 2 to 4 carbonatoms and having at least 1 and preferably from 1 to 2 sites of doublebond unsaturation. This term includes, by way of example, bi-vinyl,allyl, and but-3-en-1-yl. Included within this term are the cis andtrans isomers or mixtures of these isomers.

The term “alkynyl” refers to straight or branched monovalent hydrocarbylgroups having from 2 to 6 carbon atoms and preferably 2 to 3 carbonatoms and having at least 1 and preferably from 1 to 2 sites of triplebond unsaturation. Examples of such alkynyl groups include acetylenyl(—C≡CH), and propargyl (—CH₂C≡CH).

The term “alkoxy” as used herein includes —O-(alkyl), wherein alkyl isdefined above.

“Aryl” means a mono-, bi-, or tricyclic aromatic group, wherein allrings of the group are aromatic and all ring atoms are carbon atoms. Forbi- or tricyclic systems, the individual aromatic rings are fused to oneanother. Examples of aryl groups are 6 and 10 membered aryls. Furtherexamples of aryl groups include, but are not limited to, phenyl,naphthalene, and anthracene.

The term “cyano” as used herein means a substituent having a carbon atomjoined to a nitrogen atom by a triple bond.

The term “deuterium” as used herein means a stable isotope of hydrogenhaving one proton and one neutron.

The term “halo” represents chloro, fluoro, bromo, or iodo. In someembodiments, halo is chloro, fluoro, or bromo. The term “halogen” asused herein refers to fluorine, chlorine, bromine, or iodine.

The term “haloalkyl” represents an alkyl group substituted with one,two, three, or more halogen atoms. Examples of haloalkyl groups includefluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl,trifluoroethyl, and trifluoropropyl.

The term “hydroxy” means an —OH group.

The term “oxo” means an ═O group and may be attached to a carbon atom ora sulfur atom.

The term “N-oxide” refers to the oxidized form of a nitrogen atom.

As used herein, the term “cycloalkyl” refers to a saturated or partiallysaturated, monocyclic, fused polycyclic, bridged polycyclic, or spiropolycyclic carbocycle having from 3 to 15 carbon ring atoms. A nonlimiting category of cycloalkyl groups are saturated or partiallysaturated, monocyclic carbocycles having from 3 to 6 carbon atoms.Illustrative examples of cycloalkyl groups include, but are not limitedto, the following moieties:

“Heterocycloalkyl” as used herein refers to a monocyclic, or fused,bridged, or spiro polycyclic ring structure that is saturated orpartially saturated and has from three to 12 ring atoms selected fromcarbon atoms and up to three heteroatoms selected from nitrogen, oxygen,and sulfur. The ring structure may optionally contain up to two oxogroups on carbon or sulfur ring members, or an N-oxide. Illustrativeheterocycloalkyl entities include, but are not limited to:

Heterocycloalkyl groups may be carbon-linked, meaning they are attachedto the remainder of the molecule via a carbon atom, or nitrogen-linked,meaning they are attached to the remainder of the molecule via anitrogen atom.

As used herein, the term “heteroaryl” refers to a monocyclic, or fusedpolycyclic, aromatic heterocycle having from three to 15 ring atoms thatare selected from carbon, oxygen, nitrogen, and sulfur. Suitableheteroaryl groups do not include ring systems that must be charged to bearomatic, such as pyrylium. Suitable 5-membered heteroaryl rings (as amonocyclic heteroaryl or as part of a polycyclic heteroaryl) have oneoxygen, sulfur, or nitrogen ring atom, or one nitrogen plus one oxygenor sulfur, or 2, 3, or 4 nitrogen ring atoms. Suitable 6-memberedheteroaryl rings (as a monocyclic heteroaryl or as part of a polycyclicheteroaryl) have 1, 2, or 3 nitrogen ring atoms. Examples of heteroarylgroups include, but are not limited to, pyridinyl, imidazolyl,imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl,tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl,benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl,quinoxalinyl, naphthyridinyl, and furopyridinyl.

Those skilled in the art will recognize that the species of heteroaryl,cycloalkyl, and heterocycloalkyl groups listed or illustrated above arenot exhaustive, and that additional species within the scope of thesedefined terms may also be selected.

As used herein, the term “substituted” means that the specified group ormoiety bears one or more suitable substituents. As used herein, the term“unsubstituted” means that the specified group bears no substituents. Asused herein, the term “optionally substituted” means that the specifiedgroup is unsubstituted or substituted by the specified number ofsubstituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system.

As used herein, the expression “one or more substituents” denotes one tomaximum possible number of substitution(s) that can occur at anyvalency-allowed position on the system. In a certain embodiment, one ormore substituent means 1, 2, 3, 4, or 5 substituents. In anotherembodiment, one or more substituent means 1, 2, or 3 substituents.

Any atom that is represented herein with an unsatisfied valence isassumed to have the sufficient number of hydrogen atoms to satisfy theatom's valence.

When any variable (e.g., alkyl or R^(a)) appears in more than one placein any formula or description provided herein, the definition of thatvariable on each occurrence is independent of its definition at everyother occurrence.

Numerical ranges, as used herein, are intended to include sequentialwhole numbers. For example, a range expressed as “from 0 to 4” or “0-4”includes 0, 1, 2, 3 and 4.

When a multifunctional moiety is shown, the point of attachment to theremainder of the formula can be at any point on the multifunctionalmoiety. In some embodiments, the point of attachment is indicated by aline or hyphen. For example, aryloxy- refers to a moiety in which anoxygen atom is the point of attachment to the core molecule while arylis attached to the oxygen atom.

The nomenclature used herein to name the subject compounds isillustrated in the Examples herein. This nomenclature has generally beenderived using the commercially-available LexiChem TK software (OpenEye,Santa Fe, N. Mex.).

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. For example, compounds of any formula given hereinmay have asymmetric or chiral centers and therefore exist in differentstereoisomeric forms. All stereoisomers, including optical isomers,enantiomers, and diastereomers, of the compounds of the general formula,and mixtures thereof, are considered to fall within the scope of theformula. Furthermore, certain structures may exist as geometric isomers(i.e., cis and trans isomers), as tautomers, or as atropisomers. Allsuch isomeric forms, and mixtures thereof, are contemplated herein aspart of the present invention. Thus, any formula given herein isintended to represent a racemate, one or more enantiomeric forms, one ormore diastereomeric forms, one or more tautomeric or atropisomericforms, and mixtures thereof.

The compounds described herein include pharmaceutically acceptable saltforms of compounds of Formula I or II. A “pharmaceutically acceptablesalt” refers to a salt form of a free acid or base of a compound ofFormula I or II that is non-toxic, is physiologically tolerable, iscompatible with the pharmaceutical composition in which it isformulated, and is otherwise suitable for formulation and/oradministration to a subject. Reference to a compound herein isunderstood to include reference to a pharmaceutically acceptable salt ofsaid compound unless otherwise indicated.

Compound salts include acidic salts formed with inorganic and/or organicacids, as well as basic salts formed with inorganic and/or organicbases. In addition, where a given compound contains both a basic moiety,such as, but not limited to, a pyridine or imidazole, and an acidicmoiety, such as, but not limited to, a carboxylic acid, one of skill inthe art will recognize that the compound may exist as a zwitterion(“inner salt”); such salts are included within the term “salt” as usedherein. Salts of the compounds of the invention may be prepared, forexample, by reacting a compound with an amount of a suitable acid orbase, such as an equivalent amount, in a medium such as one in which thesalt precipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, isonicotinates, lactates, maleates,methanesulfonates, naphthalenesulfonates, nitrates, oxalates,phosphates, propionates, salicylates, succinates, sulfates, tartarates,thiocyanates, toluenesulfonates (also known as tosylates) and the like.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like.

Additionally, acids and bases which are generally considered suitablefor the formation of pharmaceutically useful salts from pharmaceuticalcompounds are discussed, for example, by P. Stahl et al., Camille G.(eds.) Handbook of Pharmaceutical Salts: Properties, Selection and Use.(2002) Zurich: Wiley-VCH; S. Berge et al., J. Pharm. Sci. (1977) 66(1)1-19. These disclosures are incorporated herein by reference thereto.

Additionally, any compound described herein is intended to refer also toany unsolvated form, or a hydrate or solvate of such a compound, andmixtures thereof, even if such forms are not listed explicitly.“Solvate” means a physical association of a compound of the inventionwith one or more solvent molecules. This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of a crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Suitable solvates include thoseformed with pharmaceutically acceptable solvents such as water, ethanol,and the like. In some embodiments, the solvent is water and the solvatesare hydrates. A compound of Formula I or II, including any hydrate orsolvate forms, may be in the form of a crystalline polymorph, anamorphous solid, or a non-solid form.

The invention also relates to pharmaceutically acceptable prodrugs ofthe compounds of Formula I or II, and treatment methods employing suchpharmaceutically acceptable prodrugs. The term “prodrug” means aprecursor of a designated compound that, following administration to asubject, yields the compound in vivo via a chemical or physiologicalprocess such as solvolysis or enzymatic cleavage, or under physiologicalconditions (e.g., a prodrug on being brought to physiological pH isconverted to the compound of Formula I or II). A “pharmaceuticallyacceptable prodrug” is a prodrug that is non-toxic, biologicallytolerable, and otherwise suitable for formulation and/or administrationto the subject. Illustrative procedures for the selection andpreparation of suitable prodrug derivatives are described, for example,in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985. Prodrugsinclude, but are not limited to, esters, amides, sulfonates, andphosphonate esters.

The present invention also relates to pharmaceutically activemetabolites of compounds of Formula I or II, and uses of suchmetabolites in the methods of the invention. A “pharmaceutically activemetabolite” means a pharmacologically active product of metabolism inthe body of a compound of Formula I or II, or salts thereof. Prodrugsand active metabolites of a compound may be determined using routinetechniques known or available in the art. See, e.g., Bertolini et al.,J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86(7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv.Drug Res. 1984, 13, 255-331; Bundgaard, Design of Prodrugs (ElsevierPress, 1985); and Larsen, Design and Application of Prodrugs, DrugDesign and Development (Krogsgaard-Larsen et al., eds., Harwood AcademicPublishers, 1991).

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S,¹⁸F, ³⁶Cl, and ¹²⁵I, respectively. Such isotopically labelled compoundsare useful in metabolic studies (for example with ¹⁴C), reaction kineticstudies (with, for example ²H or ³H), detection or imaging techniques[such as positron emission tomography (PET) or single-photon emissioncomputed tomography (SPECT)] including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or ¹¹C labeled compound may be particularly suitablefor PET or SPECT studies. Further, substitution with heavier isotopessuch as deuterium (i.e., ²H) may afford certain therapeutic advantagesresulting from greater metabolic stability, for example increased invivo half-life or reduced dosage requirements. Isotopically labeledcompounds of this invention and prodrugs thereof can generally beprepared by carrying out the procedures disclosed in the schemes or inthe examples and preparations described below by substituting a readilyavailable isotopically labeled reagent for a non-isotopically labeledreagent. Further, substitution with heavier isotopes such as deuterium(i.e., ²H) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements. Isotopically labeled compounds of thisinvention and prodrugs thereof can generally be prepared by carrying outthe procedures disclosed in the schemes or in the examples andpreparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent.

The use of the terms “salt,” “solvate,” “polymorph,” “prodrug,” and thelike, with respect to the compounds described herein is intended toapply equally to the salt, solvate, polymorph, and prodrug forms ofenantiomers, stereoisomers, rotamers, tautomers, atropisomers, andracemates of the inventive compounds.

Also contemplated herein are methods of synthesizing compounds ofFormula I or II.

Compounds of the Invention

In some embodiments of (a) Formula I or (b) Formula II, R^(a) isC₁₋₆alkyl optionally substituted with one or more R^(b) substituents. Insome embodiments, R^(a) is methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, or isopentyl, each optionallysubstituted with one or more R^(b) substituents. In some embodiments,R^(a) is C₁₋₆alkyl optionally substituted with one or two R^(b)substituents.

In some embodiments, each R^(b) is independently —OH, methoxy, ethoxy,—NR^(d)R^(e), —C(O)NR^(d)R^(e), thiomethyl, thioethyl, methanesulfonyl,ethanesulfonyl, cyano, fluoro, chloro, bromo, pyrrolyl, pyrazolyl,imidazolyl, furanyl, thiophenyl, triazolyl, tetrazolyl, oxazolyl, orthiazolyl. In other embodiments, each R^(b) is independently —OH,—C(O)NHCH₃, —CF₃, methoxy, ethoxy, fluoro, —C(O)NH₂, —C(O)N(CH₃)₂,—N(CH₃)₂, methanesulfonyl, thiomethyl, cyano, pyrazolyl,6-oxa-1-azaspiro[3.3]heptan-1-yl, azetidinyl, 3-hydroxyazetidinyl,pyrrolidinyl, or hydroxyethylamino.

In other embodiments, R^(a) is C₁₋₆alkenyl or C₁₋₆alkynyl. In someembodiments, R^(a) is ethenyl, isopropenyl, or propynyl.

In some embodiments, R^(a) is halo. In some embodiments, R^(a) is bromo,chloro, fluoro, or iodo.

In other embodiments, R^(a) is —C(O)R^(c); —NR^(d)R^(e);—C(O)NR^(d)R^(e); —C(S)NR^(d)R^(e); —C(═N—OH)—C₁₋₄alkyl; or—SO₂C₁₋₄alkyl. In other embodiments, R^(a) is —C(O)NR^(d)R^(e).

In some embodiments, R^(c) is methyl, ethyl, propyl, isopropyl, butyl,fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, oxetanyl, tetrahydrofuranyl, ortetrahydropyranyl. In other embodiments, R^(c) is ethyl, cyclopropyl,methyl, oxetanyl, or trifluoromethyl.

In some embodiments, R^(d) is H, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, or tert-butyl. In some embodiments, R^(e) is H, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyanomethyl,trifluoroethyl, hydroxyethyl, 2-hydroxy-1-methylethyl, hydroxypropyl,cyclopropyl, hydroxy, methoxy, or oxetanylmethyl. In other embodiments,R^(d) and R^(e) taken together with the nitrogen to which they areattached form azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or6-oxa-1-azaspiro[3.3]heptan-1-yl, each optionally substituted withC₁₋₄alkyl or —OH.

In other embodiments, R^(a) is cyano.

In other embodiments, R^(a) is C₃₋₆cycloalkyl optionally substitutedwith one or more R^(f) substituents. In some embodiments, R^(a) iscyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionallysubstituted with one or more R^(f) substituents. In other embodiments,R^(a) is cyclopropyl, optionally substituted with one or more R^(f)substituents.

In some embodiments, each R^(f) is independently: methyl, ethyl, propyl,or isopropyl, each optionally substituted with —OH, cyano, methoxy, orethoxy; C₁₋₄fluoroalkyl; —CONH₂; or cyano. In other embodiments, eachR^(f) is independently hydroxymethyl, methyl, cyano, trifluoromethyl,cyanomethyl, methoxymethyl, fluoromethyl, hydroxymethyl,1-hydroxy-1-methyl-ethyl, or —CONH₂.

In some embodiments, R^(a) is a phenyl, monocyclic heteroaryl, orheterocycloalkyl ring, each ring optionally substituted with one or moreR^(g) substituents. In other embodiments, R^(a) is a phenyl, pyrrolyl,furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl,triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or pyrimidinyl,each optionally substituted with one or more R^(g) substituents. In someembodiments, R^(a) is optionally substituted with one or two R^(g)substituents. In some embodiments, each R^(g) is independently methyl,ethyl, propyl, isopropyl, —CF₃, fluoro, chloro, —NH₂, —OCH₃, cyano, or—OH. In other embodiments, each R^(g) is independently fluoro, methyl,—NH₂, —CF₃, chloro, methoxy, or cyano.

In some embodiments, R^(a) and R¹ taken together with the carbons towhich they are attached form a 5- to 7-membered ring, optionallycontaining an O or NH, and optionally substituted with one or more R^(h)substituents. In other embodiments, R^(a) and R¹ taken together with thecarbons to which they are attached form cyclopentenyl, cyclohexenyl,dihydrofuranyl, dihydropyranyl, dihydropyrrolyl, or tetrahydropyridine,each optionally substituted with one or more R^(h) substituents. In someembodiments, each R^(h) is independently: methyl, ethyl, or propyl, eachoptionally substituted with hydroxy, cyano, methoxy, or —C(O)N(CH₃)₂;—C(O)NR^(i)R^(j); or cyano. In other embodiments, each R^(h) isindependently hydroxypropyl, hydroxyethyl, hydroxymethyl, methyl, cyano,methoxymethyl, —C(O)NH₂, or —CH₂C(O)N(CH₃)₂. Alternatively, two R^(h)groups attached to the same carbon are taken together with the carbon towhich they are attached to form cyclopentyl or a carbonyl.

In some embodiments, R¹ is H, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, fluoromethyl, fluoromethyl,trifluoromethyl, fluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl. In other embodiments, R¹ is H, methyl,isopropyl, trifluoromethyl, or cyclopropyl.

In some embodiments, R² is R^(m). In other embodiments, R² is —OR^(m).In other embodiments, R² is —NR^(m)R^(n). In some embodiments, R^(m) isphenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl,triazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, thiophenyl,thiazolyl, isothiazolyl, indolyl, indazolyl, quinolinyl, orisoquinolinyl, each optionally substituted with one or more R^(s)substituents. In other embodiments, R^(m) is phenyl, naphthyl, pyridyl,indazolyl, or isoquinolinyl, each optionally substituted with one ormore R^(s) substituents. In other embodiments, R^(m) is pyrazolyl,optionally substituted with one or more R^(s) substituents. In otherembodiments, R^(m) is phenyl, optionally substituted with one or moreR^(s) substituents. In other embodiments, R^(m) is optionallysubstituted with one or two R^(s) substituents. In some embodiments,each R^(s) is independently methyl, ethyl, propyl, isopropyl, butyl,fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl,trifluoroethyl, methoxy, ethoxy, isopropoxy, hydroxymethyl,hydroxyethyl, trifluoromethoxy, fluoro, chloro, bromo, iodo, cyano,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —NHSO₂C₁₋₂alkyl, or—SO₂C₁₋₂alkyl. In other embodiments, each R^(s) is independently fluoro,chloro, trifluoromethyl, cyano, methyl, methoxy, cyclopropyl, —NHSO₂CH₃,fluoroethyl, ethyl, propyl, difluoromethyl, hydroxymethyl, fluoromethyl,or methanesulfonyl.

In other embodiments, R² is R^(m) and R^(m) is

wherein at least one of X¹, X², and X³ is N, and the other two areindependently N, NR^(r), O, S, or C—R^(r);

-   R^(p) and R^(r) are each independently H; C₁₋₄haloalkyl; C₁₋₄alkyl    optionally substituted with —OH; halo; cyano; or C₃₋₆cycloalkyl; and-   R^(q) is H or fluoro;-   or R^(q) and R^(r) taken together with the carbons to which they are    attached form phenyl, optionally substituted with halo.

In some embodiments, X¹ and X² are each N and X³ is C—R^(r). In otherembodiments, X² is N and X¹ and X³ are each independently C—R^(r). Inother embodiments, X¹, X², and X³ are each N.

In some embodiments, R^(p) and R^(r) are each independently H,fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl,trifluoroethyl, methyl, ethyl, hydroxymethyl, hydroxyethyl, chloro,cyano, cyclopropyl, cyclobutyl, or cyclopentyl. In other embodiments,R^(p) is trifluoromethyl, chloro, methyl, hydroxyethyl, cyclopropyl,cyano, difluoromethyl, or ethyl. In other embodiments, R^(r) is ethyl,trifluoromethyl, methyl, chloro, H, hydroxyethyl, cyclopropyl, or cyano.

In some embodiments, R^(q) is H or fluoro. In other embodiments, R^(q)and R^(r) taken together with the carbons to which they are attachedform phenyl, optionally substituted with fluoro.

In some embodiments, R^(n) is H, fluoromethyl, difluoromethyl,trifluoromethyl, fluoroethyl, difluoroethyl, or trifluoroethyl, or ismethyl or ethyl optionally substituted with —OH, methoxy, or ethoxy. Inother embodiments, R^(n) is H, methyl, ethyl, fluoroethyl,difluoroethyl, or trifluoroethyl.

In some embodiments, R^(m) and R^(n) taken together with the nitrogen towhich they are attached form dihydroindole, optionally substituted withmethyl or fluoro.

In some embodiments, R³ is H. In other embodiments, R³ is methyl.

In some embodiments, R⁴ is H. In other embodiments, R⁴ is fluoro.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-A):

wherein

-   R^(a) is —C(O)NR^(d)R^(e);    -   wherein R^(d) is H or C₁₋₄alkyl;    -   R^(e) is H; C₁₋₄alkyl optionally substituted with —CN, —CF₃,        —OH, or a monocyclic heterocycloalkyl; C₃₋₆cycloalkyl; —OH; or        —OC₁₋₄alkoxy;    -   or R^(d) and R^(e) taken together with the nitrogen to which        they are attached form a heterocycloalkyl, optionally        substituted with C₁₋₄alkyl or —OH;-   R¹ is selected from the group consisting of H, C₁₋₆alkyl,    C₁₋₄haloalkyl, and C₃₋₆cycloalkyl;-   R² is —R^(m), —OR^(m), or —NR^(m)R^(n);    -   wherein R^(m) is aryl or heteroaryl, each optionally substituted        with one or more R^(s) substituents;        -   wherein each R^(s) substituent is independently selected            from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl,            C₁₋₄alkoxy, C₁₋₄alkyl-OH, C₁₋₄haloalkoxy, halo, cyano,            C₃₋₆cycloalkyl, —NHSO₂C₁₋₄alkyl, and —SO₂C₁₋₄alkyl;    -   R^(n) is H, C₁₋₄haloalkyl, or C₁₋₄alkyl optionally substituted        with —OH or C₁₋₄alkoxy;        -   or R^(m) and R^(n) taken together with the nitrogen to which            they are attached form a pyrrolidine or piperidine ring,            optionally substituted with C₁₋₄alkyl and optionally fused            to phenyl, wherein said phenyl is optionally substituted            with halo;-   R³ is H or methyl; and-   R⁴ is H or fluoro;-   or a pharmaceutically acceptable salt thereof.

In some embodiments of compounds of Formula (I-A), R^(d) is H, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl. In someembodiments, R^(e) is H, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert-butyl, cyanomethyl, trifluoroethyl, hydroxyethyl,2-hydroxy-1-methylethyl, hydroxypropyl, cyclopropyl, hydroxy, methoxy,or oxetanylmethyl. In other embodiments, R^(d) and R^(e) taken togetherwith the nitrogen to which they are attached form azetidinyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, or6-oxa-1-azaspiro[3.3]heptan-1-yl, each optionally substituted withC₁₋₄alkyl or —OH.

In some embodiments, R¹ is H, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, fluoromethyl, fluoromethyl,trifluoromethyl, fluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl. In other embodiments, R¹ is H, methyl,isopropyl, trifluoromethyl, or cyclopropyl.

In some embodiments, R² is R^(m). In other embodiments, R² is —OR^(m).In other embodiments, R² is —NR^(m)R^(n). In some embodiments, R^(m) isphenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl,triazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, thiophenyl,thiazolyl, isothiazolyl, indolyl, indazolyl, quinolinyl, orisoquinolinyl, each optionally substituted with one or more R^(s)substituents. In other embodiments, R^(m) is phenyl, naphthyl, pyridyl,indazolyl, or isoquinolinyl, each optionally substituted with one ormore R^(s) substituents. In other embodiments, R^(m) is pyrazolyl,optionally substituted with one or more R^(s) substituents. In otherembodiments, R^(m) is phenyl, optionally substituted with one or moreR^(s) substituents. In other embodiments, R^(m) is optionallysubstituted with one or two R^(s) substituents. In some embodiments,each R^(s) is independently methyl, ethyl, propyl, isopropyl, butyl,fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl,trifluoroethyl, methoxy, ethoxy, isopropoxy, hydroxymethyl,hydroxyethyl, trifluoromethoxy, fluoro, chloro, bromo, iodo, cyano,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —NHSO₂C₁₋₂alkyl, or—SO₂C₁₋₂alkyl. In other embodiments, each R^(s) is independently fluoro,chloro, trifluoromethyl, cyano, methyl, methoxy, cyclopropyl, —NHSO₂CH₃,fluoroethyl, ethyl, propyl, difluoromethyl, hydroxymethyl, fluoromethyl,or me thanesulfonyl.

In other embodiments, R² is R^(m) and R^(m) is

wherein at least one of X¹, X², and X³ is N, and the other two areindependently N, NR^(r), O, S, or C—R^(r);

-   R^(p) and R^(r) are each independently H; C₁₋₄haloalkyl; C₁₋₄alkyl    optionally substituted with —OH; halo; cyano; or C₃₋₆cycloalkyl; and-   R^(q) is H or fluoro;-   or R^(q) and R^(r) taken together with the carbons to which they are    attached form phenyl, optionally substituted with halo.

In some embodiments, X¹ and X² are each N and X³ is C—R^(r). In otherembodiments, X² is N and X¹ and X³ are each independently C—R^(r). Inother embodiments, X¹, X², and X³ are each N.

In some embodiments, R^(p) and R^(r) are each independently H,fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl,trifluoroethyl, methyl, ethyl, hydroxymethyl, hydroxyethyl, chloro,cyano, cyclopropyl, cyclobutyl, or cyclopentyl. In other embodiments,R^(p) is trifluoromethyl, chloro, methyl, hydroxyethyl, cyclopropyl,cyano, difluoromethyl, or ethyl. In other embodiments, R^(r) is ethyl,trifluoromethyl, methyl, chloro, H, hydroxyethyl, cyclopropyl, or cyano.

In some embodiments, R^(q) is H or fluoro. In other embodiments, R^(q)and R^(r) taken together with the carbons to which they are attachedform phenyl, optionally substituted with fluoro.

In some embodiments, R^(n) is H, fluoromethyl, difluoromethyl,trifluoromethyl, fluoroethyl, difluoroethyl, or trifluoroethyl, or ismethyl or ethyl optionally substituted with —OH, methoxy, or ethoxy. Inother embodiments, R^(n) is H, methyl, ethyl, fluoroethyl,difluoroethyl, or trifluoroethyl.

In some embodiments, R^(m) and R^(n) taken together with the nitrogen towhich they are attached form dihydroindole, optionally substituted withmethyl or fluoro.

In some embodiments, R³ is H. In other embodiments, R³ is methyl.

In some embodiments, R⁴ is H. In other embodiments, R⁴ is fluoro.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-B):

wherein

-   R^(a) is cyclopropyl, optionally substituted with one or more R^(f)    substituents;    -   each R^(f) substituent is independently selected from the group        consisting of: C₁₋₄alkyl optionally substituted with —OH, cyano,        or C₁₋₄alkoxy; C₁₋₄haloalkyl; —CONH₂; and cyano; and-   R¹ is selected from the group consisting of H, C₁₋₆alkyl,    C₁₋₄haloalkyl, and C₃₋₆cycloalkyl;-   R² is —R^(m), —OR^(m), or —NR^(m)R^(n);    -   wherein R^(m) is aryl or heteroaryl, each optionally substituted        with one or more R^(s) substituents;        -   wherein each R^(s) substituent is independently selected            from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl,            C₁₋₄alkoxy, C₁₋₄alkyl-OH, C₁₋₄haloalkoxy, halo, cyano,            C₃₋₆cycloalkyl, —NHSO₂C₁₋₄alkyl, and —SO₂C₁₋₄alkyl;    -   R^(n) is H, C₁₋₄haloalkyl, or C₁₋₄alkyl optionally substituted        with —OH or C₁₋₄alkoxy;        -   or R^(m) and R^(n) taken together with the nitrogen to which            they are attached form a pyrrolidine or piperidine ring,            optionally substituted with C₁₋₄alkyl and optionally fused            to phenyl, wherein said phenyl is optionally substituted            with halo;-   R³ is H or methyl; and-   R⁴ is H or fluoro;-   or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (I-B), each R^(f) is independently:methyl, ethyl, propyl, or isopropyl, each optionally substituted with—OH, cyano, methoxy, or ethoxy; C₁₋₄fluoroalkyl; —CONH₂; or cyano. Inother embodiments, each R^(f) is independently hydroxymethyl, methyl,cyano, trifluoromethyl, cyanomethyl, methoxymethyl, fluoromethyl,hydroxymethyl, 1-hydroxy-1-methyl-ethyl, or —CONH₂. In some embodiments,R^(a) is cyclopropyl, optionally substituted with one or two R^(f)substituents.

In some embodiments, R¹ is H, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, fluoromethyl, fluoromethyl,trifluoromethyl, fluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl. In other embodiments, R¹ is H, methyl,isopropyl, trifluoromethyl, or cyclopropyl.

In some embodiments, R² is R^(m). In other embodiments, R² is —OR^(m).In other embodiments, R² is —NR^(m)R^(n). In some embodiments, R^(m) isphenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl,triazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, thiophenyl,thiazolyl, isothiazolyl, indolyl, indazolyl, quinolinyl, orisoquinolinyl, each optionally substituted with one or more R^(s)substituents. In other embodiments, R^(m) is phenyl, naphthyl, pyridyl,indazolyl, or isoquinolinyl, each optionally substituted with one ormore R^(s) substituents. In other embodiments, R^(m) is pyrazolyl,optionally substituted with one or more R^(s) substituents. In otherembodiments, R^(m) is phenyl, optionally substituted with one or moreR^(s) substituents. In other embodiments, R^(m) is optionallysubstituted with one or two R^(s) substituents. In some embodiments,each R^(s) is independently methyl, ethyl, propyl, isopropyl, butyl,fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl,trifluoroethyl, methoxy, ethoxy, isopropoxy, hydroxymethyl,hydroxyethyl, trifluoromethoxy, fluoro, chloro, bromo, iodo, cyano,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —NHSO₂C₁₋₂alkyl, or—SO₂C₁₋₂alkyl. In other embodiments, each R^(s) is independently fluoro,chloro, trifluoromethyl, cyano, methyl, methoxy, cyclopropyl, —NHSO₂CH₃,fluoroethyl, ethyl, propyl, difluoromethyl, hydroxymethyl, fluoromethyl,or me thanesulfonyl.

In other embodiments, R² is R^(m) and R^(m) is

wherein at least one of X¹, X², and X³ is N, and the other two areindependently N, NR^(r), O, S, or C—R^(r);

-   R^(p) and R^(r) are each independently H; C₁₋₄haloalkyl; C₁₋₄alkyl    optionally substituted with —OH; halo; cyano; or C₃₋₆cycloalkyl; and-   R^(q) is H or fluoro;-   or R^(q) and R^(r) taken together with the carbons to which they are    attached form phenyl, optionally substituted with halo.

In some embodiments, X¹ and X² are each N and X³ is C—R^(r). In otherembodiments, X² is N and X¹ and X³ are each independently C—R^(r). Inother embodiments, X¹, X², and X³ are each N.

In some embodiments, R^(p) and R^(r) are each independently H,fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl,trifluoroethyl, methyl, ethyl, hydroxymethyl, hydroxyethyl, chloro,cyano, cyclopropyl, cyclobutyl, or cyclopentyl. In other embodiments,R^(p) is trifluoromethyl, chloro, methyl, hydroxyethyl, cyclopropyl,cyano, difluoromethyl, or ethyl. In other embodiments, R^(r) is ethyl,trifluoromethyl, methyl, chloro, H, hydroxyethyl, cyclopropyl, or cyano.

In some embodiments, R^(q) is H or fluoro. In other embodiments, R^(q)and R^(r) taken together with the carbons to which they are attachedform phenyl, optionally substituted with fluoro.

In some embodiments, R^(n) is H, fluoromethyl, difluoromethyl,trifluoromethyl, fluoroethyl, difluoroethyl, or trifluoroethyl, or ismethyl or ethyl optionally substituted with —OH, methoxy, or ethoxy. Inother embodiments, R^(n) is H, methyl, ethyl, fluoroethyl,difluoroethyl, or trifluoroethyl.

In some embodiments, R^(m) and R^(n) taken together with the nitrogen towhich they are attached form dihydroindole, optionally substituted withmethyl or fluoro.

In some embodiments, R³ is H. In other embodiments, R³ is methyl.

In some embodiments, R⁴ is H. In other embodiments, R⁴ is fluoro.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-C):

-   R^(a) is a monocyclic heteroaryl ring, optionally substituted with    one or more R^(g) substituents;    -   each R^(g) substituent is independently selected from the group        consisting of C₁₋₄alkyl, —CF₃, halo, —NH₂, —OCH₃, cyano, and        —OH;-   R¹ is selected from the group consisting of H, C₁₋₆alkyl,    C₁₋₄haloalkyl, and C₃₋₆cycloalkyl;-   R² is —R^(m), —OR^(m), or —NR^(m)R^(n);    -   wherein R^(m) is aryl or heteroaryl, each optionally substituted        with one or more R^(s) substituents;        -   wherein each R^(s) substituent is independently selected            from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl,            C₁₋₄alkoxy, C₁₋₄alkyl-OH, C₁₋₄haloalkoxy, halo, cyano,            C₃₋₆cycloalkyl, —NHSO₂C₁₋₄alkyl, and —SO₂C₁₋₄alkyl;    -   R^(n) is H, C₁₋₄haloalkyl, or C₁₋₄alkyl optionally substituted        with —OH or C₁₋₄alkoxy;        -   or R^(m) and R^(n) taken together with the nitrogen to which            they are attached form a pyrrolidine or piperidine ring,            optionally substituted with C₁₋₄alkyl and optionally fused            to phenyl, wherein said phenyl is optionally substituted            with halo;-   R³ is H or methyl; and-   R⁴ is H or fluoro;-   or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (I-C), R^(a) is pyrrolyl, furanyl,thiophenyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl,pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or pyrimidinyl, eachoptionally substituted with one or more R^(g) substituents. In someembodiments, R^(a) is optionally substituted with one or two R^(g)substituents. In some embodiments, each R^(g) is independently methyl,ethyl, propyl, isopropyl, —CF₃, fluoro, chloro, —NH₂, —OCH₃, cyano, or—OH. In other embodiments, each R^(g) is independently fluoro, methyl,—NH₂, —CF₃, chloro, methoxy, or cyano.

In some embodiments, R¹ is H, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, fluoromethyl, fluoromethyl,trifluoromethyl, fluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl. In other embodiments, R¹ is H, methyl,isopropyl, trifluoromethyl, or cyclopropyl.

In some embodiments, R² is R^(m). In other embodiments, R² is —OR^(m).In other embodiments, R² is —NR^(m)R^(n). In some embodiments, R^(m) isphenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl,triazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, thiophenyl,thiazolyl, isothiazolyl, indolyl, indazolyl, quinolinyl, orisoquinolinyl, each optionally substituted with one or more R^(s)substituents. In other embodiments, R^(m) is phenyl, naphthyl, pyridyl,indazolyl, or isoquinolinyl, each optionally substituted with one ormore R^(s) substituents. In other embodiments, R^(m) is pyrazolyl,optionally substituted with one or more R^(s) substituents. In otherembodiments, R^(m) is phenyl, optionally substituted with one or moreR^(s) substituents. In other embodiments, R^(m) is optionallysubstituted with one or two R^(s) substituents. In some embodiments,each R^(s) is independently methyl, ethyl, propyl, isopropyl, butyl,fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl,trifluoroethyl, methoxy, ethoxy, isopropoxy, hydroxymethyl,hydroxyethyl, trifluoromethoxy, fluoro, chloro, bromo, iodo, cyano,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —NHSO₂C₁₋₂alkyl, or—SO₂C₁₋₂alkyl. In other embodiments, each R^(s) is independently fluoro,chloro, trifluoromethyl, cyano, methyl, methoxy, cyclopropyl, —NHSO₂CH₃,fluoroethyl, ethyl, propyl, difluoromethyl, hydroxymethyl, fluoromethyl,or me thanesulfonyl.

In other embodiments, R² is R^(m) and R^(m) is

wherein at least one of X¹, X², and X³ is N, and the other two areindependently N, NR^(r), O, S, or C—R^(r);

-   R^(p) and R^(r) are each independently H; C₁₋₄haloalkyl; C₁₋₄alkyl    optionally substituted with —OH; halo; cyano; or C₃₋₆cycloalkyl; and-   R^(q) is H or fluoro;-   or R^(q) and R^(r) taken together with the carbons to which they are    attached form phenyl, optionally substituted with halo.

In some embodiments, X¹ and X² are each N and X³ is C—R^(r). In otherembodiments, X² is N and X¹ and X³ are each independently C—R^(r). Inother embodiments, X¹, X², and X³ are each N.

In some embodiments, R^(p) and R^(r) are each independently H,fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl,trifluoroethyl, methyl, ethyl, hydroxymethyl, hydroxyethyl, chloro,cyano, cyclopropyl, cyclobutyl, or cyclopentyl. In other embodiments,R^(p) is trifluoromethyl, chloro, methyl, hydroxyethyl, cyclopropyl,cyano, difluoromethyl, or ethyl. In other embodiments, R^(r) is ethyl,trifluoromethyl, methyl, chloro, H, hydroxyethyl, cyclopropyl, or cyano.

In some embodiments, R^(q) is H or fluoro. In other embodiments, R^(q)and R^(r) taken together with the carbons to which they are attachedform phenyl, optionally substituted with fluoro.

In some embodiments, R^(n) is H, fluoromethyl, difluoromethyl,trifluoromethyl, fluoroethyl, difluoroethyl, or trifluoroethyl, or ismethyl or ethyl optionally substituted with —OH, methoxy, or ethoxy. Inother embodiments, R^(n) is H, methyl, ethyl, fluoroethyl,difluoroethyl, or trifluoroethyl.

In some embodiments, R^(m) and R^(n) taken together with the nitrogen towhich they are attached form dihydroindole, optionally substituted withmethyl or fluoro.

In some embodiments, R³ is H. In other embodiments, R³ is methyl.

In some embodiments, R⁴ is H. In other embodiments, R⁴ is fluoro.

In some embodiments, compounds described herein are compounds of FormulaII or pharmaceutically acceptable salts thereof. Compounds of Formula IIinclude those in which each variable is defined independently asdescribed herein for Formula I, I-A, I-B, or I-C, or combinations ofsaid definitions. Additional embodiments of Formula II include compoundsin which R^(a) is —SCH₃, —CH₂-cyclopropyl, difluorocyclopropyl,hydroxycyclopropyl, —OCH₂CF₃, —CH═CH—CN, or —CH═CH—CONH₂. Additionalembodiments of Formula II include compounds in which R¹ is chloro,methoxy, cyano, ethoxy, trifluoroethoxy, or acetyl. Additionalembodiments of Formula II include compounds in which R^(s) isfluoro-isopropenyl, ethynyl, hydroxycyclopropyl, fluorocyclopropyl,—NH₂, —NO₂, or thiazolyl.

In other embodiments are compounds of Formula III:

wherein:

-   -   R¹⁰ is C₁₋₄alkyl, C₁₋₄haloalkyl, or cyano, or C₃₋₆cycloalkyl        optionally substituted with —C₁₋₄alkyl-OH,    -   R¹¹ is C₁₋₄alkyl; or R¹⁰ and R¹¹ taken together with the carbons        to which they are attached form a C₅₋₆cycloalkyl;    -   R¹² is —H or halo; and    -   R¹³ is phenyl, optionally substituted with one or more        substituents selected from the group consisting of halo,        C₁₋₄haloalkyl, and cyano;        and pharmaceutically acceptable salts thereof.

Additional embodiments include pharmaceutical compositions comprising atleast one compound of Formula III, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable excipient, and a method oftreating a subject suffering from a disease or medical conditionmediated by NMDA receptor activity, comprising administering to thesubject in need of such treatment an effective amount of at least onecompound of Formula III, or a pharmaceutically acceptable salt thereof.

Embodiments of the invention also include compounds in which eachvariable is defined independently as described above.

In certain embodiments, the compound of Formula I or II is a compoundselected from the group consisting of the compounds in Table 1, andpharmaceutically acceptable salts thereof:

TABLE 1 Ex. Chemical Name 1.1N-(cyanomethyl)-7-((4-fluorophenoxy)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 1.27-(4-Fluorophenoxymethyl)-N,2-dimethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide 1.33-[(Azetidin-1-yl)carbonyl]-7-(4-fluorophenoxymethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one 1.4N-ethyl-7-(4-fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide 1.57-(4-Fluorophenoxymethyl)-2-methyl-5-oxo-N-(2,2,2-trifluoroethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide 1.67-(3,4-Difluorophenoxymethyl)-N,2-dimethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide 1.7N-ethyl-7-(4-fluorophenoxymethyl)-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide 1.87-((4-fluorophenoxy)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 1.97-((4-fluorophenoxy)methyl)-N-hydroxy-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 1.107-(4-Fluorophenoxymethyl)-2-methyl-5-oxo-N-(propan-2-yl)-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide 1.117-(4-Fluorophenoxymethyl)-N-(2-hydroxyethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide 1.127-(4-Fluorophenoxymethyl)-N-(1-hydroxypropan-2-yl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide 1.137-((4-fluorophenoxy)methyl)-2-methyl-N-(oxetan-3-ylmethyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 1.147-((4-fluorophenoxy)methyl)-N-(3-hydroxypropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 1.15N-cyclopropyl-7-((4-fluorophenoxy)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 1.167-((4-fluorophenoxy)methyl)-N-methoxy-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 1.177-(4-Fluorophenoxymethyl)-N,2-dimethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carbothioamide 2.17-((4-fluorophenoxy)methyl)-2-methyl-3-propionyl-5H-thiazolo[3,2-a]pyrimidin-5-one2.27-((4-fluorophenoxy)methyl)-3-(1-hydroxypropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 2.37-(4-Fluorophenoxymethyl)-3-(1-hydroxyethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one 2.47-(4-Fluorophenoxymethyl)-3-(2-hydroxypropan-2-yl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one 2.53-acetyl-7-((4-fluorophenoxy)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one2.62-(7-((4-fluorophenoxy)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)-N-methylacetamide 2.73-Cyclopropanecarbonyl-7-(4-fluorophenoxymethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one 2.87-(4-Fluorophenoxymethyl)-3-[1-(hydroxyimino)ethyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one 2.97-((4-fluorophenoxy)methyl)-2-methyl-3-(oxetane-3-carbonyl)-5H-thiazolo[3,2-a]pyrimidin-5-one 2.107-((4-fluorophenoxy)methyl)-2-methyl-3-(2,2,2-trifluoro-1-hydroxyethyl)-5H-thiazolo[3,2-a]pyrimidin-5-one 2.117-(4-Fluorophenoxymethyl)-2-methyl-3-(trifluoroacetyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one 3.12-cyclopropyl-N-ethyl-7-((4-fluorophenoxy)methyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 3.27-(4-Fluorophenoxymethyl)-N-methyl-5-oxo-2-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide 3.32-Cyclopropyl-7-(4-fluorophenoxymethyl)-N-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide 3.4N-Ethyl-7-(4-fluorophenoxymethyl)-5-oxo-2-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide 3.57-((4-fluorophenoxy)methyl)-N-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 3.6N-ethyl-7-[[(5-fluoropyridin-2-yl)oxy]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide 4.17-(4-Fluorophenoxymethyl)-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one 4.27-(4-Fluorophenoxymethyl)-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (enantiomer 1) 4.37-(4-Fluorophenoxymethyl)-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (enantiomer 2) 4.47-((3-fluorophenoxy)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 4.57-((4-fluorophenoxy)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 4.67-(2,4-Difluorophenoxymethyl)-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one 4.77-(3,4-Difluorophenoxymethyl)-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one 4.87-(4-Chlorophenoxymethyl)-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one 4.97-[[(5-Fluoropyridin-2-yl)oxy]methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one 4.103-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-7-((4-(trifluoromethyl)phenoxy)methyl)-5H-thiazolo[3,2-a]pyrimidin-5-one 4.117-((4-fluorophenoxy)methyl)-2-methyl-3-(oxazol-2-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 4.127-((2-fluorophenoxy)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 4.134-((3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methoxy)benzonitrile 4.147-((4-fluorophenoxy)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-5H-thiazolo[3,2-a]pyrimidin-5-one 4.157-((4-fluorophenoxy)methyl)-2-methyl-3-(1H-pyrazol-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 4.167-((4-fluorophenoxy)methyl)-2-methyl-3-(4H-1,2,4-triazol-3-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 4.173-cyclopropyl-7-[(4-fluorophenoxy)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one4.18cis-2-[7-(4-Fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropane-1-carbonitrile 4.18Atrans-2-[7-(4-Fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropane-1-carbonitrile 4.19cis-2-[7-(4-Fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropane-1-carbonitrile (enantiomer 1) 4.20cis-2-[7-(4-Fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropane-1-carbonitrile (enantiomer 2) 4.21trans-2-[7-(4-Fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropane-1-carbonitrile (enantiomer 1) 4.22trans-2-[7-(4-Fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropane-1-carbonitrile (enantiomer 2) 4.237-(4-Fluorophenoxymethyl)-3-[cis-2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one 4.24trans-7-(4-Fluorophenoxymethyl)-2-methyl-3-[2-(trifluoromethyl)cyclopropyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one 4.257-(4-Fluorophenoxymethyl)-2-methyl-3-(2-methylcyclopropyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one 4.26trans-2-[2-[7-(4-Fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropyl]acetonitrile 4.277-(4-Fluorophenoxymethyl)-3-[2-(methoxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one 4.283-(2-(fluoromethyl)cyclopropyl)-7-((4-fluorophenoxy)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 4.296-fluoro-7-((4-fluorophenoxy)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 4.307-(4-Fluorophenoxymethyl)-3-(3-hydroxypropyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one 4.317-(4-Fluorophenoxymethyl)-3-(methoxymethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one 4.327-((4-fluorophenoxy)methyl)-3-(3-hydroxyoxetan-3-yl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 4.337-(4-Fluorophenoxymethyl)-3-(4-hydroxybutan-2-yl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one 4.347-(4-Fluorophenoxymethyl)-3-[2-(2-hydroxypropan-2-yl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one 5.17-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-pyrimidin-5-yl-thiazolo[3,2-a]pyrimidin-5-one 5.27-(((4-fluorophenyl)(methyl)amino)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 5.37-(((4-fluorophenyl)(2,2,2-trifluoroethyl)amino)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 5.47-(((3,4-difluorophenyl)(ethyl)amino)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 5.57-((ethyl(3-fluorophenyl)amino)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 5.67-(((2,2-difluoroethyl)(4-fluorophenyl)amino)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 5.77-((ethyl(pyridine-2-yl)amino)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 5.87-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-3-(thiazol-2-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 5.97-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-3-(thiophen-2-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 5.103-(ethyl((2-methyl-5-oxo-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)amino)benzonitrile 5.113-(2-aminopyridin-3-yl)-7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 5.127-((ethyl(pyridine-2-yl)amino)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 5.137-((4-fluorophenylamino)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 5.143-butyl-7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 5.152-cyclopropyl-7-[(N-ethyl-4-fluoro-anilino)methyl]-3-pyrimidin-5-yl-thiazolo[3,2-a]pyrimidin-5-one 5.162-ethyl-7-((ethyl(4-fluorophenyl)amino)methyl)-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 5.177-((ethyl(4-fluorophenyl)amino)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 5.187-((ethyl(4-fluorophenyl)amino)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (enantiomer 1) 5.197-((ethyl(4-fluorophenyl)amino)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (enantiomer 2) 5.207-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-thiazol-4-yl-thiazolo[3,2-a]pyrimidin-5-one 5.217-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-(3-pyridyl)thiazolo[3,2-a]pyrimidin-5-one 5.227-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-phenyl-thiazolo[3,2-a]pyrimidin-5-one5.237-[(N-ethyl-4-fluoro-anilino)methyl]-2,3-dimethyl-thiazolo[3,2-a]pyrimidin-5-one5.247-[(N-ethyl-4-fluoro-anilino)methyl]-3-(5-fluoro-3-pyridyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 5.257-[(N-ethyl-4-fluoro-anilino)methyl]-3-(2-fluoro-3-pyridyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 5.263-cyclopropyl-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 5.277-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-pyrazin-2-yl-thiazolo[3,2-a]pyrimidin-5-one 5.28 7-[(N-ethyl-4-fluoro-anilino)methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]thiazolo[3,2-a]pyrimidin-5-one 5.297-[(N-ethyl-4-fluoro-anilino)methyl]-3-isopropenyl-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 5.307-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-pyridazin-4-yl-thiazolo[3,2-a]pyrimidin-5-one 5.313-(5-chloro-3-pyridyl)-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 5.327-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-(4-pyridyl)thiazolo[3,2-a]pyrimidin-5-one 5.337-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-(1-methylpyrazol-4-yl)thiazolo[3,2-a]pyrimidin-5-one 5.347-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-(1H-pyrazol-4-yl)thiazolo[3,2-a]pyrimidin-5-one 5.355-[7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]pyridine-3-carbonitrile 5.367-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-[5-(trifluoromethyl)-3-pyridyl]thiazolo[3,2-a]pyrimidin-5-one 5.377-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-oxazol-2-yl-thiazolo[3,2-a]pyrimidin-5-one 5.387-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-3-(trifluoromethyl)-5H-thiazolo[3,2-a]pyrimidin-5-one 5.397-((ethyl(4-fluorophenyl)amino)methyl)-3-(trans-2-(fluoromethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 5.403-ethyl-7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 5.417-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-3-propyl-5H-thiazolo[3,2-a]pyrimidin-5-one 5.427-[[4-fluoro-N-(2-fluoroethyl)anilino]methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one (enantiomer 1) 5.437-[[4-fluoro-N-(2-fluoroethyl)anilino]methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one (enantiomer 2) 5.447-((ethyl(4-fluorophenyl)amino)methyl)-3-(furan-3-yl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 5.457-((ethyl(4-fluorophenyl)amino)methyl)-3-(furan-2-yl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 5.467-((5-fluoro-2-methylindolin-1-yl)methyl)-3-(furan-2-yl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 5.477-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-3-(thiophen-3-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 5.487-((5-fluoro-2-methylindolin-1-yl)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 5.497-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-3-(4-methylthiazol-2-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 5.507-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-3-(6-oxo-1,6-dihydropyridin-3-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 5.513-(6-aminopyridin-3-yl)-7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 5.527-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-3-(prop-1-ynyl)-5H-thiazolo[3,2-a]pyrimidin-5-one 5.537-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-3-vinyl-5H-thiazolo[3,2-a]pyrimidin-5-one 5.543-bromo-2-cyclopropyl-7-[(N-ethyl-4-fluoro-anilino)methyl]thiazolo[3,2-a]pyrimidin-5-one 5.553-(3,5-difluorophenyl)-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 5.567-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-(1-methylpyrazol-3-yl)thiazolo[3,2-a]pyrimidin-5-one 5.573-(2-amino-4-pyridyl)-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 5.587-[(N-ethyl-4-fluoro-anilino)methyl]-3-(5-methoxy-3-pyridyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 6.17-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-3-morpholino-5H-thiazolo[3,2-a]pyrimidin-5-one 6.23-(dimethylamino)-7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 6.37-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-3-(pyrrolidin-1-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 7.17-(((3,4-difluorophenyl)(ethyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile 7.27-((ethyl(3-fluorophenyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile 7.37-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carbonitrile 7.47-[(N-ethyl-4-fluoro-anilino)methyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3-carbonitrile7.57-((5-fluoro-2-methylindolin-1-yl)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile 7.67-(((3-cyanophenyl)(ethyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile 7.77-((ethyl(pyridin-2-yl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile 7.82-methyl-7-((2-methylindolin-1-yl)methyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile 7.97-(((3,5-difluorophenyl)(ethyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile 8.16-[(N-ethyl-4-fluoro-anilino)methyl]-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one 8.22-[(N-ethyl-4-fluoro-anilino)methyl]-6,7,8,9-tetrahydropyrimido[2,1-b][1,3]benzothiazol-4-one 8.36-[(N-ethyl-4-fluoro-anilino)methyl]-1-(hydroxymethyl)-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one 8.46-[(N-ethyl-4-fluoro-anilino)methyl]-1-(hydroxymethyl)-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one (enantiomer 1) 8.56-[(N-ethyl-4-fluoro-anilino)methyl]-1-(hydroxymethyl)-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one (enantiomer 2) 8.66-[(N-ethyl-4-fluoro-anilino)methyl]spiro[2,3-dihydrocyclopenta[3,4]thiazolo[1,4-a]pyrimidine-1,1′-cyclopentane]-8-one 8.76-[(N-ethyl-4-fluoro-anilino)methyl]-2,3-dihydrocyclopenta[3,4]thiazolo[1,4-a]pyrimidine-1,8-dione 8.86-[(N-ethyl-4-fluoro-anilino)methyl]-1,1-dimethyl-2,3-dihydrocyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one 8.92-[(N-ethyl-4-fluoro-anilino)methyl]-8,9-dihydro-6H-pyrano[3,4]thiazolo[1,4-a]pyrimidin-4-one 8.102-[(N-ethyl-4-fluoro-anilino)methyl]-7-methyl-8,9-dihydro-6H-pyrido[3,4]thiazolo[1,4-a]pyrimidin-4-one 8.116-[(N-ethyl-4-fluoro-anilino)methyl]-8-oxo-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidine-1-carboxamide 8.126-[(N-ethyl-4-fluoro-anilino)methyl]-8-oxo-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidine-1-carbonitrile 8.132-[6-[(N-ethyl-4-fluoro-anilino)methyl]-8-oxo-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-1-yl]acetonitrile 8.146-[(N-ethyl-4-fluoro-anilino)methyl]-1-(2-hydroxyethyl)-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one 8.152-((ethyl(4-fluorophenyl)amino)methyl)-6-(methoxymethyl)-7,8-dihydrocyclopenta[4,5]thiazolo[3,2-a]pyrimidin-4(6H)-one 8.162-[6-[(N-ethyl-4-fluoro-anilino)methyl]-8-oxo-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-1-yl]acetamide 9.13-cyclohexyl-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one 9.27-[(N-ethyl-4-fluoro-anilino)methyl]-3-isopropyl-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 9.33-cyclopentyl-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 9.47-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-tetrahydropyran-4-yl-thiazolo[3,2-a]pyrimidin-5-one 10.13-cyclobutyl-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 10.23-tert-butyl-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 10.33-acetyl-7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 10.47-[(N-ethyl-4-fluoro-anilino)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 10.57-[(N-ethyl-4-fluoro-anilino)methyl]-3-(1-hydroxy-1-methyl-ethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 10.67-[(N-ethyl-4-fluoro-anilino)methyl]-3-(1-hydroxyethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 10.73-[(dimethylamino)methyl]-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one 10.83-(azetidin-1-ylmethyl)-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 10.97-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-(pyrrolidin-1-ylmethyl)thiazolo[3,2-a]pyrimidin-5-one 10.107-[(N-ethyl-4-fluoro-anilino)methyl]-3-[(3-hydroxyazetidin-1-yl)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 10.117-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-(2,2,2-trifluoro-1-hydroxy-ethyl)thiazolo[3,2-a]pyrimidin-5-one 10.127-((ethyl(4-fluorophenyl)amino)methyl)-3-(hydroxymethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 10.137-[[ethyl(4-fluorophenyl)amino]methyl]-3-(methoxymethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one 10.147-[[Ethyl(4-fluorophenyl)amino]methyl]-2-methyl-3-(1H-pyrazol-1-ylmethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one 10.157-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-(methylsulfonylmethyl)thiazolo[3,2-a]pyrimidin-5-one 10.163-(ethoxymethyl)-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 10.172-[7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]acetonitrile 10.183-tert-butyl-7-[(N-ethyl-4-fluoro-anilino)methyl]thiazolo[3,2-a]pyrimidin-5-one10.197-[(N-ethyl-4-fluoro-anilino)methyl]-3-(1-hydroxy-1-methyl-ethyl)thiazolo[3,2-a]pyrimidin-5-one 10.207-[(N-ethyl-4-fluoro-anilino)methyl]-3-(1-hydroxyethyl)thiazolo[3,2-a]pyrimidin-5-one10.217-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-(6-oxa-1-azaspiro[3.3]heptan-1-ylmethyl)thiazolo[3,2-a]pyrimidin-5-one 10.227-[(N-ethyl-4-fluoro-anilino)methyl]-3-[(2-hydroxyethylamino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 10.233-(ethyl((3-(hydroxymethyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)amino)benzonitrile 10.243-[ethyl-[[3-(methoxymethyl)-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl]methyl]amino]benzonitrile 10.257-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-3-((methylthio)methyl)-5H-thiazolo[3,2-a]pyrimidin-5-one 11.13-chloro-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one 11.27-[(N-ethyl-4-fluoro-anilino)methyl]-3-fluoro-2-methyl-thiazolo[3,2-a]pyrimidin-5-one11.37-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one11.47-[(N-ethyl-4-fluoro-anilino)methyl]-3-iodo-2-methyl-thiazolo[3,2-a]pyrimidin-5-one11.53-chloro-7-[(N-ethyl-4-fluoro-anilino)methyl]thiazolo[3,2-a]pyrimidin-5-one11.6 7-[(N-ethylanilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one12.13-(1,3-dihydroxypropyl)-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 12.27-[(N-ethyl-4-fluoro-anilino)methyl]-3-(1-fluoro-3-hydroxy-propyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 12.33-(1,3-dihydroxypropyl)-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one (enantiomer 1) 12.43-(1,3-dihydroxypropyl)-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one (enantiomer 2) 12.53-(1,2-dihydroxyethyl)-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 13.17-[(N-ethyl-4-fluoro-anilino)methyl]-3-(3-hydroxypropyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 13.27-((Ethyl(4-fluorophenyl)amino)methyl)-3-(3-methoxypropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 13.37-((Ethyl(4-fluorophenyl)amino)methyl)-3-(4-hydroxybutyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 13.47-((Ethyl(4-fluorophenyl)amino)methyl)-3-(2-hydroxyethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 13.57-[[Ethyl(4-fluorophenyl)amino]methyl]-3-(2-methoxyethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one 13.63-(7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)propanamide 13.73-[7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]propanenitrile 13.83-[7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N,N-dimethyl-propanamide 13.97-[[Ethyl(4-fluorophenyl)amino]methyl]-3-(3-hydroxy-3-methylbutyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one 14.12-[7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarboxamide 14.22-[7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarboxamide 15.17-((5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one15.2 7-((3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one15.3 7-((3-chloro-5-methyl-1H-pyrazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one15.4 7-((5-chloro-3-methyl-1H-pyrazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one15.53-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-7-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-5H-thiazolo[3,2-a]pyrimidin-5-one 15.67-((1H-indazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 15.77-((5-(2-hydroxyethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one15.87-((3-(2-hydroxyethyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one15.97-((3-cyclopropyl-4-fluoro-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one15.107-((5-cyclopropyl-4-fluoro-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one15.117-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one15.127-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one15.13 7-[(5-cyclopropyl-3-methyl-pyrazol-1-yl)methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one(enantiomer 1) 15.147-[(5-cyclopropyl-3-methyl-pyrazol-1-yl)methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one(enantiomer 2) 15.157-[(3-cyclopropyl-5-methyl-pyrazol-1-yl)methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one(enantiomer 1) 15.167-[(3-cyclopropyl-5-methyl-pyrazol-1-yl)methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one(enantiomer 2) 15.177-[(3,5-dicyclopropylpyrazol-1-yl)methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 15.187-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-6-fluoro-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one15.191-((3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-5-carbonitrile15.207-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-6-fluoro-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one15.211-[[3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl]methyl]-5-methyl-pyrazole-3-carbonitrile 15.227-[[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one15.237-[(6-fluoroindazol-1-yl)methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 15.247-[[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-isopropyl-thiazolo[3,2-a]pyrimidin-5-one15.257-[(3,5-dimethylpyrazol-1-yl)methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 15.267-[(5-fluoroindazol-1-yl)methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 15.275-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 15.287-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 15.297-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 15.307-((3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 15.312-methyl-3-(pyrimidin-5-yl)-7-((5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-5H-thiazolo[3,2-a]pyrimidin-5-one 15.322-methyl-7-((5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 15.337-((3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 15.347-((1H-indazol-1-yl)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 16.17-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-N,2-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 16.27-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-N,2-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 16.37-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-N-ethyl-5-oxo-2-(trifluoromethyl)-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 16.47-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-N-ethyl-5-oxo-2-(trifluoromethyl)-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 16.57-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-N-ethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 16.62-cyclopropyl-7-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-N-ethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 16.72-cyclopropyl-7-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-N-ethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 17.12-methyl-5-oxo-7-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile 17.27-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile 17.37-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile 18.13-(1-hydroxyethyl)-2-methyl-7-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-5H-thiazolo[3,2-a]pyrimidin-5-one 18.23-acetyl-7-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 18.33-acetyl-7-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 18.43-(2-hydroxypropan-2-yl)-2-methyl-7-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-5H-thiazolo[3,2-a]pyrimidin-5-one 18.57-((5-fluoro-3-methyl-1H-indazol-1-yl)methyl)-3-(1-hydroxyethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 19.17-(1-(5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one19.27-(1-(5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)-3-(2-(hydroxymethyl)-1-methylcyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 20.13-((3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile 20.23-((6-fluoro-3-(2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile 20.32-fluoro-3-((3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile 20.43-(trans-2-(hydroxymethyl)cyclopropyl)-7-(isoquinolin-4-ylmethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 20.53-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-7-(3-(trifluoromethyl)benzyl)-5H-thiazolo[3,2-a]pyrimidin-5-one 20.63-((3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)-4-methylbenzonitrile 20.74-fluoro-3-((3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile 20.83-fluoro-5-((3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile 20.92-fluoro-5-((3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile 20.103-[[3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl]methyl]-4-methoxy-benzonitrile 20.113-(2-(hydroxymethyl)cyclopropyl)-2-methyl-7-(4-(trifluoromethyl)benzyl)-5H-thiazolo[3,2-a]pyrimidin-5-one 20.124-((3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)picolinonitrile 20.134-cyclopropyl-3-((3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile 21.17-(3-cyanobenzyl)-N,2-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide21.27-(3-cyano-2-fluorobenzyl)-N,2-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.37-(3-chloro-2-fluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.4N-ethyl-7-(2-fluoro-3-(trifluoromethyl)benzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.5N-ethyl-7-(2-fluoro-3-methylbenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.67-(2-chloro-5-cyanobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.7N-ethyl-2-methyl-5-oxo-7-(3-(trifluoromethyl)benzyl)-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.87-(3-cyanobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.97-(3-cyano-2-fluorobenzyl)-2-cyclopropyl-N-ethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.107-(3-cyano-5-fluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.117-(3-cyanobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.12N-ethyl-7-(2-fluoro-3-(trifluoromethyl)benzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.137-(3-cyano-2-fluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.147-[(3-chloro-2-fluoro-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.15N,2-dimethyl-5-oxo-7-[[3-(trifluoromethyl)phenyl]methyl]thiazolo[3,2-a]pyrimidine-3-carboxamide 21.167-[(3-chlorophenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.177-[[2-cyclopropyl-5-(trifluoromethyl)phenyl]methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.18N-ethyl-2-methyl-5-oxo-7-((6-(trifluoromethyl)pyridine-2-yl)methyl)-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.19N-ethyl-7-(2-ethyl-4,5-difluorobenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.207-[[3-(difluoromethyl)-2-fluoro-phenyl]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.21N-ethyl-7-(2-ethyl-4,5-difluorobenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.227-((6-cyanopyridin-2-yl)methyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.237-[[3-(difluoromethyl)-2-fluoro-phenyl]methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.247-[[2-fluoro-3-(hydroxymethyl)phenyl]methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.257-(3-cyclopropyl-2-fluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.267-(3-cyano-2-fluorobenzyl)-N-ethyl-6-fluoro-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.277-(3-cyano-2-fluorobenzyl)-6-fluoro-N,N-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.287-(3-cyano-2-fluorobenzyl)-N-ethyl-6-fluoro-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.296-fluoro-7-(2-fluoro-3-(trifluoromethyl)benzyl)-N,2-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.307-(5-cyano-2-methylbenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.317-(5-cyano-2-fluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.327-(2-chloro-5-fluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.337-(3-cyano-2-fluorobenzyl)-N-ethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.34N-ethyl-7-(5-fluoro-2-(trifluoromethyl)benzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.35N-ethyl-2-methyl-7-(naphthalen-1-ylmethyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.36N-ethyl-7-(5-fluoro-2-methylbenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.377-(3-cyano-4-fluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.38N-ethyl-2-methyl-7-((1-methyl-1H-indazol-4-yl)methyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.39N-ethyl-2-methyl-7-(3-(methylsulfonamido)benzyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.407-(5-cyano-2-(trifluoromethyl)benzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.417-(4-chloro-2-methylbenzyl)-N,2-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.427-(2,5-difluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.437-(3-cyanobenzyl)-2-cyclopropyl-N-ethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.44N-ethyl-7-(2-fluorobenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.457-(2,3-difluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.46N-ethyl-7-(3-fluorobenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.477-[(3-chloro-4-fluoro-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.487-[(2,5-dichlorophenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.49N,2-dimethyl-5-oxo-7-[[3-(trifluoromethoxy)phenyl]methyl]thiazolo[3,2-a]pyrimidine-3-carboxamide 21.507-[(5-cyano-2-fluoro-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.517-[(3-chloro-5-cyano-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.527-[(3-cyclopropylphenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.537-[(2,5-difluorophenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.547-[(3,4-difluorophenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.557-[(2,3-difluorophenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.567-[(4-chloro-2-fluoro-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.577-[(2,4-dichlorophenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.587-[(3-fluoro-4-methyl-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.597-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.607-[(2-cyclopropyl-4-fluoro-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.617-(5-cyano-2-(2-fluoroethyl)benzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.627-(2-chloro-3-cyanobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.63N-ethyl-7-(6-ethyl-2,3-difluorobenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.647-(5-cyano-2-ethylbenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.657-(2-cyclopropyl-5-fluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.667-(5-cyano-2-cyclopropylbenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.67N-ethyl-7-(5-fluoro-2-propylbenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.687-[[2-fluoro-3-(fluoromethyl)phenyl]methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 22.1N-ethyl-7-(1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 22.2N-ethyl-7-(2-fluoro-3-(trifluoromethyl)benzyl)-N,2-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 23.13-((3-(2-cyanocyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile 23.23-((3-(2-cyanocyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)-2-fluorobenzonitrile 23.36-((3-(2-cyanocyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)picolinonitrile 23.43-((3-(2-cyanocyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)-4-methoxybenzonitrile 24.12-methyl-3-(pyrimidin-5-yl)-7-(3-(trifluoromethyl)benzyl)-5H-thiazolo[3,2-a]pyrimidin-5-one 24.27-(2-fluoro-3-(trifluoromethyl)benzyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 24.32-fluoro-3-((2-methyl-5-oxo-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile 24.43-((3-cyclopropyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)-2-fluorobenzonitrile 24.57-(isoquinolin-4-ylmethyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 24.63-((2-methyl-5-oxo-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile 24.77-(5-fluoro-2-methoxybenzyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 24.82-fluoro-3-((3-(furan-2-yl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile 24.93-bromo-2-methyl-7-(3-(methylsulfonyl)benzyl)-5H-thiazolo[3,2-a]pyrimidin-5-one25.17-(3-cyano-2-fluorobenzyl)-2-methyl-5-oxo-N-(2,2,2-trifluoroethyl)-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 25.2N-(cyanomethyl)-7-(2-fluoro-3-(trifluoromethyl)benzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 26.17-(3-cyanobenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile26.27-(2-fluoro-3-(trifluoromethyl)benzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile 27.110-(4-fluorophenoxymethyl)-3-(hydroxymethyl)-7-thia-1,9-diazatricyclo[6.4.0.0{circumflex over( )}[2,6]]dodeca-2(6),8,10-trien-12-one 27.210-(4-Fluorophenoxymethyl)-3-(2-hydroxyethyl)-7-thia-1,9-diazatricyclo[6.4.0.0{circumflex over( )}[2,6]]dodeca-2(6),8,10-trien-12-one 27.37-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-methylsulfonyl-thiazolo[3,2-a]pyrimidin-5-one 27.43-(hydroxymethyl)-10-[[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-7-thia-1,9-diazatricyclo[6.4.0.0{circumflex over( )}[2,6]]dodeca-2(6),8,10-trien-12-one 27.510-{[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-7-thia-1,9-diazatricyclo[6.4.0.0{circumflex over( )}{2,6}]dodeca-2(6),8,10-trien-12-one 27.610-{[3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-7-thia-1,9-diazatricyclo[6.4.0.0{circumflex over( )}{2,6}]dodeca-2(6),8,10-trien-12-one 27.710-{[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-3,3-dimethyl-7-thia-1,9-diazatricyclo[6.4.0.0{circumflex over( )}{2,6}]dodeca-2(6),8,10-trien-12-one 27.810-{[3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-3,3-dimethyl-7-thia-1,9-diazatricyclo[6.4.0.0{circumflex over( )}{2,6}]dodeca-2(6),8,10-trien-12-one 27.910-{[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-3,3-dimethyl-7-thia-1,9-diazatricyclo[6.4.0.0{circumflex over( )}{2,6}]dodeca-2(6),8,10-trien-12-one 27.103-((3-acetyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)-2-fluorobenzonitrile 27.117-(2-fluoro-3-(trifluoromethyl)benzyl)-3-(1-hydroxyethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (enantiomer 1) 27.127-(2-fluoro-3-(trifluoromethyl)benzyl)-3-(1-hydroxyethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (enantiomer 2) 27.133-((3-acetyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile27.147-(2-fluoro-3-(trifluoromethyl)benzyl)-3-(hydroxymethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 27.157-(2-fluoro-3-(trifluoromethyl)benzyl)-2-methyl-3-((methylamino)methyl)-5H-thiazolo[3,2-a]pyrimidin-5-one

In certain embodiments, the compound of Formula I or II is a compoundselected from the group consisting of the compounds in Table 2, andpharmaceutically acceptable salts thereof:

TABLE 2 Ex. Chemical Name  17-[(3-cyclopropyl-2-fluoro-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  2N-ethyl-2-methyl-5-oxo-7-[(2,3,6-trifluorophenyl)methyl]thiazolo[3,2-a]pyrimidine-3-carboxamide  32-fluoro-3-[(2-methyl-3-oxazol-2-yl-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl)methyl]benzonitrile  47-[(5-cyano-3-cyclopropyl-2-fluoro-phenyl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  5N-ethyl-7-[(2-fluoro-3-methoxy-phenyl)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  67-[(3-cyclopropyl-2-fluoro-phenyl)methyl]-6-fluoro-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  72-[7-[(3-chloro-2-fluoro-phenyl)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-acetamide  87-[(3-chloro-2-fluoro-phenyl)methyl]-N-ethyl-6-fluoro-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  7-[(4,5-difluoro-2-methoxy-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  102-fluoro-3-[[2-methyl-3-(2-methylcyclopropyl)-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl]methyl]benzonitrile  112-[7-[(3-cyclopropyl-2-fluoro-phenyl)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-acetamide  13N-ethyl-6-fluoro-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  147-[[2-chloro-5-(trifluoromethyl)phenyl]methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  157-[(3-cyano-2-fluoro-phenyl)methyl]-6-fluoro-2-methyl-5-oxo-N-(2,2,2-trifluoroethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide  167-[(2-chloro-4,5-difluoro-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  177-[[4,5-difluoro-2-(2-fluoroethyl)phenyl]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  182-[7-[[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-acetamide  192-[7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-acetamide  207-[(5-chloro-3-methyl-pyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  217-[(3-chloro-5-methyl-pyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  227-[(3-chloro-5-cyclopropyl-pyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  237-[(5-chloro-3-cyclopropyl-pyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  243-[2-(hydroxymethyl)cyclopropyl]-2-methyl-7-[[4-(trifluoromethyl)thiazol-2-yl]methyl]]thiazolo[3,2-a]pyrimidin-5-one  252-[7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-acetamide  26N-ethyl-2-methyl-7-[[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  27N-ethyl-2-methyl-7-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  287-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-2-methyl-5-oxothiazolo[3,2-a]pyrimidine-3-carboxamide  297-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-2-methyl-5-oxothiazolo[3,2-a]pyrimidine-3-carboxamide  307-[[3-(difluoromethyl)-2-fluoro-phenyl]methyl]-6-fluoro-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  317-[[3-(difluoromethyl)-2-fluoro-phenyl]methyl]-N-ethyl-6-fluoro-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  327-(4-bicyclo[4.2.0]octa-1,3,5-trienylmethyl)-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  33N-ethyl-7-[[2-fluoro-3-(1-hydroxycyclopropyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  35N-ethyl-7-[[2-fluoro-3-(1-fluorocyclopropyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  36N-ethyl-7-[[2-fluoro-3-[1-(fluoromethyl)vinyl]phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  377-[(2-ethynyl-4,5-difluoro-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  382-fluoro-3-[[2-methyl-5-oxo-3-[2-(trifluoromethyl)cyclopropyl]thiazolo[3,2-a]pyrimidin-7-yl]methyl]benzonitrile  393-[[3-(2,2-difluorocyclopropyl)-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl]methyl]-2-fluoro-benzonitrile  40N-ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide  417-[(3-cyano-2-fluoro-phenyl)methyl]-N-ethyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide  427-[[3-(difluoromethyl)-2-fluoro-phenyl]methyl]-N-ethyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide  437-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide  447-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide  45N-ethyl-7-[[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide  46N-ethyl-7-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide  477-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-3-(1H-imidazol-2-yl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one  497-[(3-cyano-2-fluoro-5-methyl-phenyl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  507-[(3-chloro-2-fluoro-phenyl)methyl]-N-ethyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide  517-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-N-(2,2,2-trifluoroethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide  522-methyl-7-[[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-N-(2,2,2-trifluoroethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide  537-[[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N-methyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide  547-[[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-N-methyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide  557-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N-methyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide  567-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-N-methyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide  577-[[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-N-(2,2,2-trifluoroethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide  587-[[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-N-(2,2,2-trifluoroethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide  602-chloro-N-ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  61N-methyl-7-[[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide  62N-methyl-7-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide  637-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-N-methyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide  647-[(3-chloro-2-fluoro-phenyl)methyl]-N-methyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide  657-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-N-(2,2,2-trifluoroethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide  667-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-N-(2,2,2-trifluoroethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide  672-methyl-7-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-N-(2,2,2-trifluoroethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide  692-chloro-7-[(3-cyano-2-fluoro-phenyl)methyl]-N-ethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  707-[(3-cyano-2-fluoro-phenyl)methyl]-N-methyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide  71N-ethyl-2-[7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]acetamide  72N,2-dimethyl-5-oxo-7-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]thiazolo[3,2-a]pyrimidine-3-carboxamide  743-[[2-chloro-5-oxo-3-[2-(trifluoromethyl)cyclopropyl]thiazolo[3,2-a]pyrimidin-7-yl]methyl]-2-fluoro-benzonitrile  752-[7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-acetamide  767-[[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  782-[7-[[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-acetamide  792-[7-[[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-acetamide  807-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-3-(methylsulfonylmethyl)thiazolo[3,2-a]pyrimidin-5-one  817-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-3-(1H-imidazol-2-ylmethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one  82N-ethyl-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  83N-ethyl-7-[(N-ethyl-4-fluoro-anilino)methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide  842-fluoro-3-[[3-(2-methylcyclopropyl)-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-7-yl]methyl]benzonitrile  853-[[2-chloro-3-(2-methylcyclopropyl)-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl]methyl]-2-fluoro-benzonitrile  87N-ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-isopropyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  882-fluoro-3-[[5-oxo-2-(trifluoromethyl)-3-[2-(trifluoromethyl)cyclopropyl]thiazolo[3,2-a]pyrimidin-7-yl]methyl]benzonitrile  896-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one  906-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one  91N-ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methoxy-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  926-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-1-(hydroxymethyl)-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one  932-ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-N-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  942-[7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile  956-[[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-1-(hydroxymethyl)-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one  967-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  977-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide  982-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-acetamide  992-[7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-acetamide 1007-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-3-(2-hydroxycyclopropyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1027-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1037-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1042-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile 1052-cyano-N-ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 1067-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-N-isopropyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 1087-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(1-hydroxy-1-methyl-ethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1097-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(1-hydroxy-1-methyl-ethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1107-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(1-hydroxyethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1117-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(1-hydroxyethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1127-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-N-sec-butyl-thiazolo[3,2-a]pyrimidine-3-carboxamide 1133-[[3-(azetidin-1-yl)-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl]methyl]-2-fluoro-benzonitrile 1147-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carbonitrile 1157-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carbonitrile 1167-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-cyclopropyl-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1177-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-cyclopropyl-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1187-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-(2-methylcyclopropyl)thiazolo[3,2-a]pyrimidin-5-one 1193-acetyl-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1203-acetyl-7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1212-chloro-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methy]-3-(2-methylcyclopropyl)thiazolo[3,2-a]pyrimidin-5-one 1227-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-pyrimidin-5-yl-thiazolo[3,2-a]pyrimidin-5-one 1237-[[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 1247-[[(5-chloro-2-pyridyl)-methyl-amino]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 1252-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile (cis enantiomer 1) 1262-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile (cis enantiomer 2) 1277-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-2-methoxy-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 1287-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-2-methoxy-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 1297-[[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-2-methoxy-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 1307-[[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-2-methoxy-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 1312-[7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile 1327-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-(1H-pyrazol-5-yl)thiazolo[3,2-a]pyrimidin-5-one 1337-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-(1H-pyrazol-5-yl)thiazolo[3,2-a]pyrimidin-5-one 1347-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-(3-pyridyl)thiazolo[3,2-a]pyrimidin-5-one 1357-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-isopropenyl-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1367-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one (trans enantiomer 1) 1377-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one (trans enantiomer 2) 1387-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(5-fluoro-3-pyridyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1397-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(5-fluoro-3-pyridyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1407-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-propanoyl-thiazolo[3,2-a]pyrimidin-5-one 1417-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-propanoyl-thiazolo[3,2-a]pyrimidin-5-one 1427-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-thiazol-2-yl-thiazolo[3,2-a]pyrimidin-5-one 143N-ethyl-7-[[(5-fluoro-2-pyridyl)-methyl-amino]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 1442-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile145 2-[7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile1462-fluoro-3-[[5-oxo-2-(trifluoromethyl)-3-[2-(trifluoromethyl)cyclopropyl]thiazolo[3,2-a]pyrimidin-7-yl]methyl]benzonitrile 147N-ethyl-7-[[ethyl-(5-fluoro-2-pyridyl)amino]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 148N-ethyl-7-[[ethyl(2-pyridyl)amino]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 1493-(5-chloro-3-pyridyl)-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1503-(5-chloro-3-pyridyl)-7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1517-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-thiazol-4-yl-thiazolo[3,2-a]pyrimidin-5-one 1527-[[5-chloro-2-pyridyl)-ethyl-amino]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 1537-[(5-cyclopropyltriazol-1-yl)methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1547-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-[2-methylcyclopropyl]thiazolo[3,2-a]pyrimidin-5-one (trans enantiomer 1)155 7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-[2-methylcyclopropyl]thiazolo[3,2-a]pyrimidin-5-one (trans enantiomer 2)1562-ethoxy-N-ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 1577-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(2-fluoro-3-pyridyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1587-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-oxazol-2-yl-thiazolo[3,2-a]pyrimidin-5-one 1597-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-oxazol-2-yl-thiazolo[3,2-a]pyrimidin-5-one 1607-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 1617-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 1622-[7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile 1637-[[(5-chloro-2-pyridyl)-methyl-amino]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1647-[(3,5-dichloropyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 165N-ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-2-(2,2,2-tnfluoroethoxy)thiazolo[3,2-a]pyrimidine-3-carboxamide 1663-acetyl-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 1673-acetyl-7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 1683-[(4-chloropyrazol-1-yl)methyl]-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1697-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-isopropenyl-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 1707-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(1H-imidazol-2-yl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1717-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-pyrimidin-5-yl-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 1727-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-pyrimidin-5-yl-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 1737-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(3-pyridyl)-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 1747-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-5-oxo-2-(2,2,2-tnfluoroethoxy)thiazolo[3,2-a]pyrimidine-3-carboxamide 1757-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-ethoxy-N-ethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 1767-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-ethoxy-N-ethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 1777-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-(2-methylpropanoyl)thiazolo[3,2-a]pyrimidin-5-one 1787-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-(2-methylpropanoyl)thiazolo[3,2-a]pyrimidin-5-one 1797-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-N-[(1R)-1-methylpropyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 1807-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-N-[(1S)-1-methylpropyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 1917-[[(4-chloro-2-pyridyl)-ethyl-amino]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 1827-[[(5-fluoro-2-pyridyl)-methyl-amino]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1837-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(methoxymethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1847-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-cyclopropyl-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 1857-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-(methylsulfonylmethyl)thiazolo[3,2-a]pyrimidin-5-one 1867-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-(pyrazol-1-ylmethyl)thiazolo[3,2-a]pyrimidin-5-one 1872-[7-[[2-chloro-5-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile 1887-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-cyclobutyl-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1897-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-cyclobutyl-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1902-[7-[[(5-chloro-2-pyridyl)-methyl-amino]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile 1917-[[ethyl-(5-fluoro-2-pyridyl)amino]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1923-chloro-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1933-chloro-7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1942-[7-[(4,5-difluoro-2-methoxy-phenyl)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile 1952-[7-[[ethyl-(5-fluoro-2-pyridyl)amino]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile 1967-[[(5-chloro-2-pyridyl)-ethyl-amino]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 1975-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]pyridine-3-carbonitrile 1987-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-(2,2,2-tnfluoroacetyl)thiazolo[3,2-a]pyrimidin-5-one 1997-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(2-methylcyclopropyl)-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 2007-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(2-methylcyclopropyl)-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 2017-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-pyrimidin-5-yl-thiazolo[3,2-a]pyrimidin-5-one 2027-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-ethyl-3-(3-pyridyl)thiazolo[3,2-a]pyrimidin-5-one 2037-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-(2,2,2-trifluoro-1-hydroxy-ethyl)thiazolo[3,2-a]pyrimidin-5-one 2047-[[5-bromo-2-pyridyl)-ethyl-amino]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 205N-ethyl-7-[[ethyl-(5-fluoro-2-pyridyl)amino]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide 2063-(azetidin-1-yl)-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 2072-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile(cis enantiomer 1) 2082-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile(cis enantiomer 2) 2092-[7-[[5-methoxy-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile 2102-[7-[[3-methoxy-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile 2113-acetyl-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-ethyl-thiazolo[3,2-a]pyrimidin-5-one 2123-acetyl-7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-ethyl-thiazolo[3,2-a]pyrimidin-5-one 2132-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-ethyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile 2142-[7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-ethyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile 2153-bromo-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 2163-bromo-7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 2173-chloro-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methoxy-thiazolo[3,2-a]pyrimidin-5-one 2183-chloro-7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methoxy-thiazolo[3,2-a]pyrimidin-5-one 2197-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-methylsulfanyl-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 2202-[7-[(N-ethyl-4-fluoro-anilino)methyl]-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-1-(hydroxymethyl)cyclopropanecarbonitrile 2217-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(cyclopropylmethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 2227-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(2-hydroxy-1-methyl-ethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 2237-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(2-hydroxy-1-methyl-ethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 2247-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(cyclopropanecarbonyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 2253-bromo-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]thiazolo[3,2-a]pyrimidin-5-one 2263-bromo-7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]thiazolo[3,2-a]pyrimidin-5-one 2277-[(3-amino-5-chloro-pyrazol-1-yl)methyl]-3-bromo-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 2287-[(5-amino-3-chloro-pyrazol-1-yl)methyl]-3-bromo-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 2292-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]acetonitrile 230N-ethyl-7-[[(5-fluoro-2-pyridyl)-methyl-amino]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide 2317-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methy;]-3-(3,3-difluoroazetidin-l-yl)-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 2337-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methoxy-3-(3-pyridyl)thiazolo[3,2-a]pyrimidin-5-one 2342-[7-[[5-bromo-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile 2353-chloro-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]thiazolo[3,2-a]pyrimidin-5-one 2363-chloro-7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]thiazolo[3,2-a]pyrimidin-5-one 2372-acetyl-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 2382-acetyl-7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 2397-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 2407-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-3-(1H-1,2,4-triazol-5-yl)thiazolo[3,2-a]pyrimidin-5-one 2412-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile 2423-acetyl-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]thiazolo[3,2-a]pyrimidin-5-one 2437-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(2,2,2-trifluoroethoxy)-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 2443-acetyl-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methoxy-thiazolo[3,2-a]pyrimidin-5-one 2453-acetyl-7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methoxy-thiazolo[3,2-a]pyrimidin-5-one 2463-bromo-7-[(5-chloro-3-nitro-pyrazol-1-yl)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 2477-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(1H-pyrazol-5-yl)-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 2487-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-thiazol-4-yl-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 2497-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(5-fluoro-3-pyridyl)-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 2507-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-propanoyl-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 2512-[7-[(3,5-dichloropyrazol-1-yl)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile 251A2-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]propanenitrile 2522-[7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]propanenitrile 2532-fluoro-3-[[3-[2-methylcyclopropyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-7-yl]methyl]benzonitrile 2547-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(3-fluoroazetidin-1-yl)-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 2553-(5-chloro-3-pyridyl)-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 2567-[(3,5-dichloropyrazol-1-yl)methyl]-N-ethyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide 2573-[[3-acetyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-7-yl]methyl]-2-fluoro-benzonitrile 2587-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-(difluoromethyl)-N-ethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 2597-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-(difluoromethyl)-N-ethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 260(Z)-3-[7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]prop-2-enenitrile 261(E)-3-[7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]prop-2-enamide 262(E)-3-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]prop-2-enenitrile 263(Z)-3-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]prop-2-enenitrile 264(E)-3-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]prop-2-enamide 265N-ethyl-7-[[5-isobutyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 2662-[2-chloro-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile (cis enantiomer 1) 2672-[2-chloro-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile (cis enantiomer 2) 2682-[2-chloro-7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile 2697-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one (trans enantiomer 1)2707-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one (trans enantiomer 2)2712-[7-[(4-chloro-1-methyl-pyrazol-3-yl)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile 2722-[2-methyl-5-oxo-7-[[3-(trifluoromethyl)pyrazol-1-yl]methyl]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile (cis enantiomer 1) 2732-[2-methyl-5-oxo-7-[[3-(trifluoromethyl)pyrazol-1-yl]methyl]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile (cis enantiomer 2) 2742-[7-[[5-bromo-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile (cis enantiomer 1) 2752-[7-[[5-bromo-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile (cis enantiomer 2) 2762-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-6-fluoro-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile(cis enantiomer 1) 2772-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-6-fluoro-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile(cis enantiomer 2) 2782-[2-methyl-7-[[1-methyl-4-(trifluoromethyl)imidazol-2-yl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile 279(E)-3-[7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]prop-2-enenitrile 2807-[(4-fluorophenoxy)methyl]-3-[[2-hydroxyethyl(methyl)amino]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 2817-[(4-fluorophenoxy)methyl]-3-[(2-hydroxyethylamino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 2822-[7-[(4-fluorophenoxy)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N,N-dimethyl-acetamide 2837-[(2-cyano-4,5-difluoro-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 2847-[(2-cyclopropyl-4,5-difluoro-phenyl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 2853-[2-(azetidin-1-yl)-2-oxo-ethyl]-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 2867-[(4-fluorophenoxy)methyl]-2-methyl-3-(4H-1,2,4-triazol-3-ylmethyl)thiazolo[3,2-a]pyrimidin-5-one 2872-[7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-propanamide 2883-[7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-propanamide 2897-[[5-chloro-2-(trifluoromethyl)phenyl]methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 2907-[(5-ethyl-1,3-benzoxazol-6-yl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 2917-[(3-chloropyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 2927-[(5-chloropyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 2932-[7-[(3-cyano-2-fluoro-phenyl)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-acetamide 294N-ethyl-7-[[2-fluoro-3-(1-hydroxypropyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 2957-[(4,5-difluoro-2-oxazol-2-yl-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 2962-fluoro-3-[(2-methyl-5-oxo-3-propanoyl-thiazolo[3,2-a]pyrimidin-7-yl)methyl]benzonitrile 2977-[[4,5-difluoro-2-(trifluoromethyl)phenyl]methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 2997-[[2-chloro-5-(trifluoromethyl)phenyl]methyl]-N-ethyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide 3007-[[2-chloro-5-(trifluoromethyl)phenyl]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 3017-[[2-chloro-5-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-N-(2,2,2-tnfluoroethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide 3033-[(2-chloro-3-cyclopropyl-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl)methyl]-2-fluoro-benzonitrile 3047-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-3-(pyrazol-1-ylmethyl)thiazolo[3,2-a]pyrimidin-5-one 305N,2-dimethyl-7-[[3-methyl-4-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 306N,2-dimethyl-7-[[5-methyl-4-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 3072-fluoro-3-[(8-oxo-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-6-yl)methyl]benzonitrile 3087-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-3-[hydroxy(thiazol-2-yl)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 3092-fluoro-3-[(3-methyl-8-oxo-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-6-yl)methyl]benzonitrile 3102-[7-[(4-fluorophenoxy)methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-acetamide 3122-fluoro-3-[[1-(hydroxymethyl)-8-oxo-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-6-yl]methyl]benzonitrile 3137-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-N-(2-hydroxy-1-methyl-ethyl)-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 3143-[[3-(2,3-dimethylcyclopropyl)-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl]methyl]-2-fluoro-benzonitrile 3156-[[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-1-(hydroxymethyl)-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one 3167-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)thiazolo[3,2-a]pyrimidin-5-one 317N-ethyl-6-fluoro-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide 3187-[(4-fluorophenoxy)methyl]-5-oxo-N-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide 319N-cyclopentyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 3207-[(4,5-dichloropyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 3217-[(3,4-dichloropyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 322N-ethyl-2-methyl-7-[[methyl(thiazol-2-yl)amino]methyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 3237-[(4-chloropyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 324N-ethyl-2-methyl-7-[[methyl-(1-methylpyrazol-4-yl)amino]methyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 3257-[(4-fluorophenoxy)methyl]-2-(trifluoromethyl)-3-[2-(trifluoromethyl)cyclopropyl]thiazolo[3,2-a]pyrimidin-5-one 3267-[[(3-ethoxy-2-pyridyl)-methyl-amino]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 3277-[[(3,5-dimethylisoxazol-4-yl)-methyl-amino]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 3283-cyclopropyl-7-[(4-fluorophenoxy)methyl]-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 3297-[(4-fluorophenoxy)methyl]-3-pyrimidin-5-yl-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 3307-[(4-fluorophenoxy)methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 3317-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-3-(4-methyl-1,2,4-triazol-3-yl)thiazolo[3,2-a]pyrimidin-5-one 3322-fluoro-3-[[5-oxo-2-(trifluoromethyl)-3-[2-(trifluoromethyl)cyclopropyl]thiazolo[3,2-a]pyrimidin-7-yl]methyl]benzonitrile 333N-ethyl-7-[[ethyl(4-pyridyl)amino]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 334N-ethyl-7-[[ethyl(3-pyridyl)amino]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 3357-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methy]-3-(2-methoxy-3-pyridyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 3362-[7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile 3377-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-isopropenyl-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 3383-(5-chloro-3-pyridyl)-7-[[(5-chloro-2-pyridyl)-methyl-amino]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 3397-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(3-pyridyl)-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 3407-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-5-oxo-2-(2,2,2-tnfluoroethoxy)thiazolo[3,2-a]pyrimidine-3-carboxamide 3417-[[3-chloro-6-(trifluoromethyl)-2-pyridyl]methyl]-2-methyl-3-(2-methylcyclopropyl)thiazolo[3,2-a]pyrimidin-5-one 3427-[(5-chloro-2-pyridyl)oxymethyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 3437-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-ethyl-3-(3-pyridyl)thiazolo[3,2-a]pyrimidin-5-one 3447-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-pyrrolidin-1-yl-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 345N-ethyl-7-[[(5-methoxy-2-pyridyl)-methyl-amino]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 3463-(2-chloro-3-pyridyl)-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 3473-(2-chloro-3-pyridyl)-7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 3487-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(3-pyridyl)thiazolo[3,2-a]pyrimidin-5-one 3497-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(3-pyridyl)thiazolo[3,2-a]pyrimidin-5-one 3507-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(3-methoxyazetidin-1-yl)-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 3517-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(cyclopropylmethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 3525-[7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]pyridine-3-carbonitrile 3532-fluoro-3-[[3-[2-methylcyclopropyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-7-yl]methyl]benzonitrile 3547-[(3,5-diisopropylpyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 3552-[7-[(4-chloro-2-methyl-pyrazol-3-yl)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile 3567-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(2-methylazetidin-1-yl)-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 3572-[7-[(3,5-dichloropyrazol-1-yl)methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile (cis enantiomer 1) 3582-[7-[(3,5-dichloropyrazol-1-yl)methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile (cis enantiomer 2) 3597-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-[2-(2-hydroxyethyl)cyclopropyl]-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one (trans enantiomer 1)3607-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-[2-(2-hydroxyethyl)cyclopropyl]-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one (trans enantiomer 2)361 3-chloro-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 3625-chloro-1-[[3-[2-methylcyclopropyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-7-yl]methyl]pyrazole-3-carbonitrile (cis enantiomer1) 3635-chloro-1-[[3-[2-methylcyclopropyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-7-yl]methyl]pyrazole-3-carbonitrile (cis enantiomer2) 3645-chloro-2-[[3-[(2-methylcyclopropyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-7-yl]methyl]pyrazole-3-carbonitrile 3657-[[5-ethoxy-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 366N-ethyl-7-[[5-isobutyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide 3672-[2-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]cyclopropyl]acetonitrile(trans enantiomer 1) 3682-[2-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]cyclopropyl]acetonitrile(trans enantiomer 2)

In certain embodiments, the compound of Formula III is a compoundselected from the group consisting of the compounds in Table 3, andpharmaceutically acceptable salts thereof:

TABLE 3 Ex. Chemical Name 123-[2-(hydroxymethyl)cyclopropyl]-2-methyl-7-[3-(trifluoromethyl)phenoxy]thiazolo[3,2-a]pyrimidin-5-one 346-fluoro-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-7-[3-(trifluoromethyl)phenoxy]thiazolo[3,2-a]pyrimidin-5-one 48N-ethyl-7-[2-fluoro-3-(trifluoromethyl)phenoxy]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 597-[2-fluoro-3-(trifluoromethyl)phenoxy]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 687-(3-cyano-2-fluoro-phenoxy)-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 733-cyclopropyl-7-[2-fluoro-3-(trifluoromethyl)phenoxy]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 772-fluoro-3-[2-methyl-5-oxo-3-[2-(trifluoromethyl)cyclopropyl]thiazolo[3,2-a]pyrimidin-7-yl]oxy-benzonitrile 867-[2-fluoro-3-(trifluoromethyl)phenoxy]-2-methyl-3-(2-methylcyclopropyl)thiazolo[3,2-a]pyrimidin-5-one 1012-[7-[2-fluoro-3-(trifluoromethyl)phenoxy]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile 1072-fluoro-3-[2-methyl-3-(2-methylcyclopropyl)-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl]oxy-benzonitrile 298N,2-dimethyl-5-oxo-7-[3-(trifluoromethyl)phenoxy]thiazolo[3,2-a]pyrimidine-3-carboxamide 302N-ethyl-2-methyl-5-oxo-7-[3-(trifluoromethyl)phenoxy]thiazolo[3,2-a]pyrimidine-3-carboxamide 3112-fluoro-3-[(8-oxo-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-6-yl)oxy]benzonitrilePharmaceutical Description

As used herein, the term “subject” encompasses mammals and non-mammals.Examples of mammals include, but are not limited to, any member of theMammalian class: humans; non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;and laboratory animals including rodents, such as rats, mice and guineapigs, and the like. Examples of non-mammals include, but are not limitedto, birds, fish and the like. In one embodiment of the presentinvention, the mammal is a human.

“Patient” encompasses a human or animal subject.

The term “inhibitor” refers to a molecule such as a compound, a drug, anenzyme activator, or a hormone that blocks or otherwise interferes witha particular biologic activity.

The term “modulator” refers to a molecule, such as a compound of thepresent invention, that increases or decreases, or otherwise affects theactivity of a given enzyme or protein.

As used herein, the terms “treat” or “treatment” encompass both“preventative” and “curative” treatment. “Preventative” treatment ismeant to indicate a postponement of development of a disease, a symptomof a disease, or medical condition, suppressing symptoms that mayappear, or reducing the risk of developing or recurrence of a disease orsymptom. “Curative” treatment includes reducing the severity of orsuppressing the worsening of an existing disease, symptom, or condition.Thus, treatment includes ameliorating or preventing the worsening ofexisting disease symptoms, preventing additional symptoms fromoccurring, ameliorating or preventing the underlying metabolic causes ofsymptoms, inhibiting the disorder or disease, e.g., arresting thedevelopment of the disorder or disease, relieving the disorder ordisease, causing regression of the disorder or disease, relieving acondition caused by the disease or disorder, or stopping the symptoms ofthe disease or disorder.

The terms “effective amount” or “therapeutically effective amount” referto a sufficient amount of the agent to provide the desired biologicalresult. That result can be reduction and/or alleviation of the signs,symptoms, or causes of a disease or medical condition, or any otherdesired alteration of a biological system. For example, an “effectiveamount” for therapeutic use is the amount of a compound, or of acomposition comprising the compound, that is required to provide aclinically relevant change in a disease state, symptom, or medicalcondition. An appropriate “effective” amount in any individual case maybe determined by one of ordinary skill in the art using routineexperimentation. Thus, the expression “effective amount” generallyrefers to the quantity for which the active substance has atherapeutically desired effect. Effective amounts or doses of thecompounds of the embodiments may be ascertained by routine methods, suchas modeling, dose escalation, or clinical trials, taking into accountroutine factors, e.g., the mode or route of administration or drugdelivery, the pharmacokinetics of the agent, the severity and course ofthe infection, the subject's health status, condition, and weight, andthe judgment of the treating physician. An exemplary dose is in therange of about 1 μg to 2 mg of active agent per kilogram of subject'sbody weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1to 35 mg/kg/day, or about 0.1 to 10 mg/kg/day. The total dosage may begiven in single or divided dosage units (e.g., BID, TID, QID).

Once improvement of the patient's disease has occurred, the dose may beadjusted for preventative or maintenance treatment. For example, thedosage or the frequency of administration, or both, may be reduced as afunction of the symptoms, to a level at which the desired therapeutic orprophylactic effect is maintained. Of course, if symptoms have beenalleviated to an appropriate level, treatment may cease. Patients may,however, require intermittent treatment on a long-term basis upon anyrecurrence of symptoms. Patients may also require chronic treatment on along-term basis.

A pharmaceutical composition according to the invention comprises atleast one compound of Formula (I), or a pharmaceutically acceptable saltthereof. The pharmaceutical compositions may further comprise one ormore pharmaceutically-acceptable excipients. Apharmaceutically-acceptable excipient is a substance that is non-toxicand otherwise biologically suitable for administration to a subject.Such excipients facilitate administration of the compounds describedherein and are compatible with the active ingredient. Examples ofpharmaceutically-acceptable excipients include stabilizers, lubricants,anti-caking agents, glidants, surfactants, diluents, anti-oxidants,binders, chelating agents, coating agents, coloring agents, bulkingagents, emulsifiers, buffers, pH modifiers, or taste-modifying agents.In preferred embodiments, pharmaceutical compositions according to theembodiments are sterile compositions. Sterile compositions includecompositions that are in accord with national and local regulationsgoverning such compositions. Pharmaceutical compositions may be preparedusing compounding techniques known or that become available to thoseskilled in the art.

The pharmaceutical compositions and compounds described herein may beformulated as solutions, emulsions, suspensions, dispersions, orinclusion complexes such as cyclodextrins in suitable pharmaceuticalsolvents or carriers, or as pills, tablets, lozenges, suppositories,sachets, dragees, granules, powders, powders for reconstitution, orcapsules along with solid carriers according to conventional methodsknown in the art for preparation of various dosage forms. Pharmaceuticalcompositions of the embodiments may be administered by a suitable routeof delivery, such as oral, parenteral, rectal, nasal, topical, or ocularroutes, or by inhalation. Preferably, the compositions are formulatedfor intravenous or oral administration.

A further embodiment of the invention is a method of preparing apharmaceutical formulation comprising mixing at least one compound ofthe present invention, and, optionally, one or more pharmaceuticallyacceptable excipients.

In certain aspects, the invention relates to methods of treatingdiseases or conditions mediated by activation or deactivation of NMDAreceptors, or which are generally mediated by NMDA receptor activity.Such disease or condition is one or more selected from the groupconsisting of pain, neuropathic pain, inflammatory pain, peripheralneuropathy, stroke, epilepsy, neurodegeneration, schizophrenia, drugaddiction, mood disorders, post-traumatic stress disorder, seizures,convulsions, age-associated memory impairment, depression, stroke,traumatic brain injury, ischemia, Alzheimer's disease, Parkinson'sdisease, Huntington's disease, amyotrophic lateral sclerosis, orCreutzfeldt-Jakob disease. In particular, the disease or condition isschizophrenia.

Still another aspect of this invention is to provide a method fortreating, preventing, inhibiting or eliminating a disease or conditionin a patient by modulating, activating, or inhibiting NMDA receptoractivity in said patient by administering a therapeutically effectiveamount of at least one compound of this disclosure, wherein said diseaseor condition is selected from the group consisting of pain, neuropathicpain, inflammatory pain, peripheral neuropathy, stroke, epilepsy,neurodegeneration, schizophrenia, drug addiction, mood disorders,post-traumatic stress disorder, seizures, convulsions, age-associatedmemory impairment, depression, stroke, traumatic brain injury, ischemia,Alzheimer's disease, Parkinson's disease, Huntington's disease,amyotrophic lateral sclerosis, or Creutzfeldt-Jakob disease.

Still another aspect of this invention is the use of a compound asdescribed herein as a positive allosteric modulator (PAM) of an NMDAreceptor. The invention includes a method of modulating and/oramplifying the activity an NMDA receptor by contacting the receptor atan allosteric binding site with at least one compound as describedherein or a pharmaceutical composition comprising such a compound.Further, compounds of the invention are useful as subtype selective forNR2A-containing NMDA receptors. The invention is also directed toward amethod of modulating an NR2A-containing NMDA receptor by contacting thereceptor with at least one compound of the invention or a pharmaceuticalcomposition comprising such a compound.

The pharmaceutical compositions and compounds described herein may beformulated as solutions, emulsions, suspensions, dispersions, orinclusion complexes such as cyclodextrins in suitable pharmaceuticalsolvents or carriers, or as pills, tablets, lozenges, suppositories,sachets, dragees, granules, powders, powders for reconstitution, orcapsules along with solid carriers according to conventional methodsknown in the art for preparation of various dosage forms. Pharmaceuticalcompositions of the embodiments may be administered by a suitable routeof delivery, such as oral, parenteral, rectal, nasal, topical, or ocularroutes, or by inhalation. Preferably, the compositions are formulatedfor intravenous or oral administration.

For oral administration, the compounds the embodiments may be providedin a solid form, such as a tablet or capsule, or as a solution,emulsion, or suspension. To prepare the oral compositions, the compoundsof the embodiments may be formulated to yield a dosage of, e.g., fromabout 0.01 to about 50 mg/kg daily, or from about 0.05 to about 20 mg/kgdaily, or from about 0.1 to about 10 mg/kg daily. Oral tablets mayinclude the active ingredient(s) mixed with compatible pharmaceuticallyacceptable excipients such as diluents, disintegrating agents, bindingagents, lubricating agents, sweetening agents, flavoring agents,coloring agents and preservative agents. Suitable inert fillers includesodium and calcium carbonate, sodium and calcium phosphate, lactose,starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol,sorbitol, and the like. Exemplary liquid oral excipients includeethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone(PVP), sodium starch glycolate, microcrystalline cellulose, and alginicacid are exemplary disintegrating agents. Binding agents may includestarch and gelatin. The lubricating agent, if present, may be magnesiumstearate, stearic acid, or talc. If desired, the tablets may be coatedwith a material such as glyceryl monostearate or glyceryl distearate todelay absorption in the gastrointestinal tract, or may be coated with anenteric coating.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, active ingredient(s) may be mixed witha solid, semi-solid, or liquid diluent. Soft gelatin capsules may beprepared by mixing the active ingredient with water, an oil such aspeanut oil or olive oil, liquid paraffin, a mixture of mono anddi-glycerides of short chain fatty acids, polyethylene glycol 400, orpropylene glycol.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions, or syrups, or may be lyophilized or presented as adry product for reconstitution with water or other suitable vehiclebefore use. Such liquid compositions may optionally contain:pharmaceutically-acceptable excipients such as suspending agents (forexample, sorbitol, methyl cellulose, sodium alginate, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel andthe like); non-aqueous vehicles, e.g., oil (for example, almond oil orfractionated coconut oil), propylene glycol, ethyl alcohol, or water;preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbicacid); wetting agents such as lecithin; and, if desired, flavoring orcoloring agents.

The inventive compositions may be formulated for rectal administrationas a suppository. For parenteral use, including intravenous,intramuscular, intraperitoneal, intranasal, or subcutaneous routes, theagents of the embodiments may be provided in sterile aqueous solutionsor suspensions, buffered to an appropriate pH and isotonicity or inparenterally acceptable oil. Suitable aqueous vehicles include Ringer'ssolution and isotonic sodium chloride. Such forms may be presented inunit-dose form such as ampoules or disposable injection devices, inmulti-dose forms such as vials from which the appropriate dose may bewithdrawn, or in a solid form or pre-concentrate that can be used toprepare an injectable formulation. Illustrative infusion doses rangefrom about 1 to 1000 μg/kg/minute of agent admixed with a pharmaceuticalcarrier over a period ranging from several minutes to several days.

For nasal, inhaled, or oral administration, the inventive pharmaceuticalcompositions may be administered using, for example, a spray formulationalso containing a suitable carrier.

For topical applications, the compounds of the present embodiments arepreferably formulated as creams or ointments or a similar vehiclesuitable for topical administration. For topical administration, theinventive compounds may be mixed with a pharmaceutical carrier at aconcentration of about 0.1% to about 10% of drug to vehicle. Anothermode of administering the agents of the embodiments may utilize a patchformulation to effect transdermal delivery.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two tofour divided doses.

Still another embodiment of the invention is a pharmaceuticalformulation comprising at least one compound of Formula I or II, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient, and further comprising one or more adjunctiveactive agent. Methods of treatment as described herein include regimesin which the compound of the invention and at least one adjunctiveactive agent are administered simultaneously or sequentially.

The expression “adjunctive active agent” generally refers to agentswhich targets the same or a different disease, symptom, or medicalcondition as the primary therapeutic agent. Adjunctive active agents maytreat, alleviate, relieve, or ameliorate side effects caused byadministration of the primary therapeutic agents.

EXAMPLES

Exemplary, non-limiting, chemical entities and methods useful inpreparing compounds of the invention will now be described by referenceto the specific examples that follow. Those skilled in the art willappreciate that other synthetic routes may be used to synthesize thecompounds according to the invention. Although specific startingmaterials and reagents are depicted and discussed herein, other startingmaterials and reagents can be easily substituted to provide a variety ofderivatives and/or reaction conditions. In addition, many of theexemplary compounds prepared by the described methods can be furthermodified in light of this disclosure using conventional chemistry wellknown to those skilled in the art.

Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Each of the reactions depicted in the reactionschemes is preferably run at a temperature from about 0° C. to thereflux temperature of the solvent used.

In the methods of preparing compounds according to the invention, it maybe advantageous to separate reaction products from one another and/orfrom starting materials. The desired products of each step or series ofsteps may be separated and/or purified to the desired degree ofhomogeneity by the techniques common in the art. Typically suchseparations involve multiphase extraction, crystallization from asolvent or solvent mixture, distillation, sublimation, orchromatography. Chromatography can involve any number of methodsincluding, for example: reverse-phase and normal phase; size exclusion;ion exchange; high, medium and low pressure liquid chromatographymethods and apparatus; small scale analytical; simulated moving bed(SMB) and preparative thin or thick layer chromatography, as well astechniques of small scale thin layer and flash chromatography.

Diastereomeric mixtures may be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers may beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride, orformation of a mixture of diastereomeric salts, for example, withtartaric acid or a chiral amine), separating the diastereomers by, forexample, fractional crystallization or chromatography, and converting(e.g., hydrolyzing or de-salting) the individual diastereomers to thecorresponding pure enantiomers. Enantiomers may also be separated by useof chiral HPLC column or prepared directly by chiral synthesis. Thechiral centers of compounds of the present invention may be designatedas “R” or “S” as defined by the IUPAC 1974 Recommendations. Enriched orpurified enantiomers can be distinguished by methods used to distinguishother chiral molecules with asymmetric carbon atoms, such as opticalrotation and circular dichroism.

General Experimental Conditions

Unless otherwise indicated, ¹H NMR spectra were recorded at ambienttemperature using a Varian Unity Inova (400 MHz) spectrometer with atriple resonance 5 mm probe. Chemical shifts are expressed in ppmrelative to tetramethylsilane. The following abbreviations have beenused: br=broad signal, s=singlet, d=doublet, dd=double doublet,t=triplet, q=quartet, m=multiplet.

Microwave experiments were carried out using a CEM Discover, SmithSynthesiser or a Biotage Initiator 60™, which uses a single-moderesonator and dynamic field tuning, both of which give reproducibilityand control. Temperatures from 40-250° C. can be achieved and pressuresof up to 30 bars can be reached.

High Pressure Liquid Chromatography-Mass Spectrometry (LCMS) experimentswas used to detect associated mass ions. The spectrometers have anelectrospray source operating in positive and negative ion mode.Additional detection was achieved using a Sedex 85 evaporative lightscattering detector.

The following examples illustrate the preparation of representativecompounds of the invention. Unless otherwise specified, all reagents andsolvents were of standard commercial grade and were used without furtherpurification. Those having skill in the art will recognize that thestarting materials, reagents, and conditions described in the examplesmay be varied and additional steps employed to produce compoundsencompassed by the present inventions.

Method 1 Example 1.1:N-(cyanomethyl)-7-((4-fluorophenoxy)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

Step 1: Methyl 3-bromo-2-oxobutanoate

To a solution of methyl 2-oxobutanoate (1.00 g, 8.61 mmol) in chloroform(20 mL) were added hydrogen bromide in acetic acid (40%, 1 mL) andbromine (1.40 g, 8.76 mmol) dropwise with stirring at room temperature.The reaction mixture was stirred for 1 h at 70° C. After cooling down toroom temperature, the resulting solution was concentrated in vacuo toafford methyl 3-bromo-2-oxobutanoate as yellow oil (1.60 g, 95%). NoLCMS signal.

Step 2: Methyl 2-amino-5-methyl-1,3-thiazole-4-carboxylate

To a solution of methyl 3-bromo-2-oxobutanoate (1.60 g, 8.20 mmol) in1,4-dioxane (30 mL) was added thiourea (625 mg, 8.21 mmol) withstirring. The resulting solution was refluxed for 3 h in an oil bath.After cooling down to room temperature, the solids were collected byfiltration and dried in vacuo to afford methyl2-amino-5-methyl-1,3-thiazole-4-carboxylate as a gray solid (900 mg,64%). LCMS (ESI): M+H⁺=173.

Step 3: Methyl7-(chloromethyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxylate

To a mixture of methyl 2-amino-5-methyl-1,3-thiazole-4-carboxylate (200mg, 1.16 mmol) and ethyl 4-chloro-3-oxobutanoate (390 mg, 2.32 mmol) wasadded polyphosphoric acid (5 mL). The reaction mixture was stirred 1 hat 110° C. The reaction was then quenched with water (20 mL). The pHvalue of the solution was adjusted to pH 8 with sodium hydroxide (aq.,10 mol/L) and extracted with dichloromethane (2×100 mL), washed withbrine, dried over anhydrous sodium sulfate and concentrated in vacuo.The residue was purified by chromatography with ethyl acetate/petroleumether (1:1) to afford methyl7-(chloromethyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxylateas a light yellow solid (120 mg, 38%). LCMS (ESI): M+H⁺=273.

Step 4: Methyl7-(4-fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxylate

To a solution of methyl7-(chloromethyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxylate(200 mg, 0.73 mmol), potassium iodide (60 mg, 0.37 mmol) and potassiumcarbonate (200 mg, 1.45 mmol) in acetonitrile (15 mL) was added4-fluorophenol (125 mg, 1.12 mmol). After stirring 2 h at 85° C., thereaction mixture was cooled down to room temperature and concentratedunder vacuum. The residue was purified by chromatography with ethylacetate/petroleum ether (1:1) to afford methyl7-(4-fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxylateas a white solid (220 mg, 86%). LCMS (ESI): M+H⁺=349; ¹H NMR (300 MHz,CDCl₃) δ 7.02-6.92 (m, 2H), 6.91-6.86 (m, 2H), 6.48 (s, 1H), 4.92 (s,2H), 3.98 (s, 3H), 2.45 (s, 3H).

Step 5:7-((4-fluorophenoxy)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxylicacid

To a solution of methyl7-(4-fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxylate(5.00 g, 14.3 mmol) in tetrahydrofuran (400 mL) and water (200 mL) wasadded lithium hydroxide (7.00 g, 167 mmol). The resulting solution wasstirred at 25° C. for 30 h. After the starting material was consumed (byTLC), the pH of the solution was adjusted to 7 with 2 N hydrogenchloride. Then the solution was concentrated in vacuo until a solidprecipitated. The solids were filtered and washed with tetrahydrofuranto afford7-((4-fluorophenoxy)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxylicacid as white solid (1.70 g, 36%). LCMS (ESI): M+H⁺=335.

Step 6:N-(Cyanomethyl)-7-(4-fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide

To a solution of7-((4-fluorophenoxy)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxylicacid (100 mg, 0.30 mmol), 2-aminoacetonitrile hydrochloride (56 mg, 0.61mmol), triethylamine (90 mg, 0.90 mmol), 4-dimethylaminopyridine (4 mg,0.03 mmol) and 1-hydroxybenzotrizole (80 mg, 0.60 mmol) inN,N-dimethylformamide (8 mL) was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (115 mg,0.6 mmol) with stirring. The resulting solution was stirred overnightand was concentrated under vacuum. The residue was purified on a silicagel column eluting with dichloromethane/methanol (30:1) to affordN-(cyanomethyl)-7-(4-fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamideas white solid (22.7 mg, 20%). LCMS (ESI): M+H⁺=373; ¹H NMR (300 MHz,DMSO-d₆) δ 9.22 (m, 1H), 7.18-7.03 (m, 4H), 6.30 (s, 1H), 5.02 (s, 2H),4.36-4.31 (m, 2H), 2.34 (s, 3H).

The following examples were prepared in a manner similar to Example 1.1:

LCMS No. Structure/Name (M + H) ¹H NMR 1.2

348.0 ¹H NMR (300 MHz, CDCl₃) δ 7.01-6.95 (m, 2H), 6.91-6.86 (m, 2H),6.44 (s, 1H), 6.01 (br, 1H), 4.91 (s, 2H), 3.09-3.04 (m, 3H), 2.42 (s,3H) 1.3

374.0 ¹H NMR (300 MHz, CDCl₃) δ 7.03-6.87 (m, 4H), 6.48 (s, 1H), 4.93(s, 2H), 4.43-4.34 (m, 1H), 4.20-4.02 (m, 2H), 3.93-3.86 (m, 1H),2.41-2.33 (m, 5H) 1.4

361.9 ¹H NMR (300 MHz, CDCl₃) δ 7.01-6.95 (m, 2H), 6.90-6.86 (m, 2H),6.45 (s, 1H), 5.89 (s, 1H), 4.91 (s, 2H), 3.57-3.50 (m, 2H), 2.42 (s,3H), 1.31-1.27 (m, 3H) 1.5

415.9 ¹H NMR (400 MHz, DMSO-d₆) δ 9.21-9.19 (m, 1H), 7.17-7.04 (m, 4H),6.29 (s, 1H), 5.01 (s, 2H), 4.05-4.14 (m, 2H), 2.33 (s, 3H) 1.6

365.95 ¹H NMR (300 MHz, DMSO-d₆) δ 8.38-8.36 (m, 1H), 7.39-7.36 (m, 1H),7.25-7.24 (m, 1H), 6.91-6.89 (m, 1H), 6.28 (s, 1H), 5.02 (s, 2H),2.77-2.74 (m, 3H), 2.29 (s, 3H) 1.7

348.0 ¹H NMR (300 MHz, CDCl₃) δ 9.64 (br, 1H), 8.03 (s, 1H), 6.87- 7.03(m, 4H), 6.58 (s, 1H), 4.96 (s, 2H), 3.42-3.51 (m, 2H), 1.24- 1.28 (m,3H) 1.8

334.1 ¹H NMR (400 MHz, DMSO-d₆) δ 7.90 (s, 1H), 7.77 (s, 1H), 7.20- 7.10(m, 2H), 7.10-6.98 (m, 2H), 6.28 (s, 1H), 5.00 (s, 2H), 2.36 (s, 3H).1.9

350.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.91 (s, 1H), 9.36 (s, 1H), 7.19-7.09 (m, 2H), 7.09-6.98 (m, 2H), 6.29 (s, 1H), 5.00 (s, 2H), 2.35 (d, J= 1.9 Hz, 3H)

The following additional compounds were prepared using the methodsdescribed above.

LCMS No. Structure/Name (M + H) ¹H NMR 1.10

376.10 ¹H NMR (300 MHz, CDCl₃) δ 7.02-6.99 (m, 2H), 6.95-6.91 (m, 2H),6.48 (s, 1H), 5.74 (s, 1H), 4.94 (s, 2H), 4.36-4.34 (m, 1H), 2.46 (s,3H), 1.32 (s, 6H) 1.11

378.0 ¹H NMR (300 MHz, CD₃OD) δ 7.04 (m, 4H), 6.45 (s, 1H), 5.01 (s,2H), 3.80-3.73 (m, 2H), 3.56- 3.51 (m, 2H), 2.46 (s, 3H) 1.12

392.0 ¹H NMR (300 MHz, CDCl₃) δ 7.01-6.96 (m, 2H), 6.91-6.85 (m, 2H),6.50 (s, 1H), 5.87-5.03 (m, 1H), 4.93 (s, 2H), 4.23-4.25 (m, 1H),4.08-03 (m, 1H), 3.55-3.50 (m, 1H), 2.45 (s, 3H), 1.30-1.27 (m, 3H) 1.13

404.0 ¹H NMR (300 MHz, CD₃OD) δ 7.09-7.00 (m, 4H), 6.44 (s, 1H), 5.01(s, 2H), 4.87-4.85 (m, 2H), 4.57-4.53 (m, 2H), 3.72-3.70 (m, 2H),3.41-3.38 (m, 1H), 2.45 (s, 3H) 1.14

392.0 ¹H NMR (300 MHz, CDCl₃) δ 7.02-6.97 (m, 2H), 6.91-6.88 (m, 2H),6.53 (br, 1H), 6.49 (s, 1H), 4.94 (s, 2H), 3.90-3.85 (m, 2H), 3.70-3.66(m, 2H), 2.46 (s, 3H), 1.95-1.89 (m, 2H) 1.15

374.0 ¹H NMR (300 MHz, CDCl₃) δ 7.01-6.95 (m, 2H), 6.89-6.85 (m, 2H),6.45 (s, 1H), 6.03 (s, 1H), 4.91 (s, 2H), 2.93-2.90 (m, 1H), 2.42 (s,3H), 0.93-0.87 (m, 2H), 0.81-0.74 (m, 2H). 1.16

364.1 ¹H NMR (400 MHz, DMSO-d₆) δ 11.50 (s, 1H), 7.19-7.09 (m, 2H),7.09-6.99 (m, 2H), 6.30 (s, 1H), 5.01 (s, 2H), 3.73 (s, 3H), 2.36 (s,3H). 1.17

363.9 ¹H NMR (300 MHz, CD₃OD) δ 7.04-6.97 (m, 4H), 6.38 (s, 1H), 5.06(s, 2H), 3.22 (s, 3H), 2.36 (s, 3H).

Method 2 Example 2.1:7-((4-fluorophenoxy)methyl)-2-methyl-3-propionyl-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of methyl7-((4-fluorophenoxy)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxylate(from Example 1.1, Step 4; 100 mg, 0.29 mmol) in tetrahydrofuran (2 mL)was added ethylmagnesium bromide (0.14 mL, 0.32 mmol). The reactionmixture was stirred for 1 h at room temperature. The reaction was thenquenched by addition of water, extracted with dichloromethane (3×30 mL),washed with brine, dried over anhydrous sodium sulfate and concentratedin vacuo. The residue was purified on a silica gel column with ethylacetate/petroleum ether (1:3) to provide7-((4-fluorophenoxy)methyl)-2-methyl-3-propionyl-5H-thiazolo[3,2-a]pyrimidin-5-oneas a white solid (91.9 mg, 92%). LCMS (ESI): M+H⁺=347.0.

Example 2.2:7-((4-fluorophenoxy)methyl)-3-(1-hydroxypropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of7-((4-fluorophenoxy)methyl)-2-methyl-3-propionyl-5H-thiazolo[3,2-a]pyrimidin-5-one(from Example 2.1; 20.0 mg, 0.060 mmol) in methanol (10 mL) was addedsodium borohydride (4.70 mg, 0.13 mmol). The reaction mixture wasstirred overnight at room temperature. The reaction was then quenched bysaturated aqueous ammonium chloride (20 mL), extracted withdichloromethane (3×30 mL), washed with brine, dried over sodium sulfateand concentrated in vacuo. The residue was purified by chromatographywith dichloromethane/methanol (50:1) to afford7-((4-fluorophenoxy)methyl)-3-(1-hydroxypropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-oneas a white solid (4.50 mg, 21%). LCMS (ESI): M+H⁺=349.0; ¹H NMR (300MHz, CD₃OD) δ 7.05-7.03 (m, 4H), 6.50 (s, 1H), 5.11-5.01 (m, 1H), 4.89(s, 2H), 2.51 (s, 3H), 1.96-1.83 (m, 2H), 0.97-0.92 (m, 3H).

The following examples were prepared in a manner similar to Example 2.1and 2.2:

LCMS No. Structure/Name (M + H) ¹H NMR 2.3

335.20 ¹H NMR (300 MHz, DMSO- d₆) δ 7.18-7.12 (m, 2H), 7.08- 7.03 (m,2H), 6.33 (s, 1H), 5.68-5.62 (m, 2H), 5.00 (s, 2H), 2.49 (s, 3H),1.43-1.41 (m, 3H) 2.4

349.10 ¹H NMR (300 MHz, CD₃OD) δ 7.18-7.13 (s, 2H), 7.08-7.05 (s, 2H),6.66 (s, 1H), 6.41 (s, 1H), 5.02 (s, 2H), 2.54 (s, 3H), 1.65 (s, 6H) 2.5

333.0  ¹H NMR (300 MHz, CD₃OD) δ 7.08-7.01 (m, 4H), 6.46 (s, 1H), 5.06(s, 2H), 2.50 (s, 3H), 2.40 (s, 3H).

Example 2.6:2-(7-((4-fluorophenoxy)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)-N-methylacetamide

Step 1:7-((4-fluorophenoxy)methyl)-3-(hydroxymethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

Into a 25-mL round bottom flask under nitrogen was added a solution ofmethyl7-((4-fluorophenoxy)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxylate(from Example 1.1, Step 5) (200 mg, 0.57 mmol) in tetrahydrofuran (20mL) and a solution of diisobutylaluminum hydride in toluene (1.1 mol/L,1 mL). The resulting solution was stirred overnight at room temperature.The reaction was quenched with water (30 mL), extracted withdichloromethane (3×50 mL), washed with brine, dried over sodium sulfateand concentrated in vacuo. The residue was purified by silica gelchromatography with dichloromethane/methanol (50:1) to afford7-((4-fluorophenoxy)methyl)-3-(hydroxymethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-oneas an off-white solid (150 mg, 77%). LCMS (ESI): M+H⁻=321.0; ¹H NMR (300MHz, CDCl₃) δ 7.02-6.87 (m, 4H), 6.48 (s, 1H), 4.93 (s, 2H), 4.76 (s,2H), 2.44 (s, 3H).

Step 2:3-(Chloromethyl)-7-(4-fluorophenoxymethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a solution of7-(4-fluorophenoxymethyl)-3-(hydroxymethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(200 mg, 0.62 mmol) in dichloromethane (5 mL) was added thionyl chloride(0.5 mL) and N,N-dimethylformamide (10 mg, 0.14 mmol). The resultingsolution was stirred overnight at room temperature and then concentratedin vacuo. The residue was purified by chromatography withdichloromethane/ethyl acetate (50/1) to afford3-(chloromethyl)-7-(4-fluorophenoxymethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas a white solid (150 mg, 71%). LCMS (ESI): M+H⁺=339.0; ¹H NMR (400 MHz,CDCl₃) δ 7.01-6.96 (m, 2H), 6.92-6.89 (m, 2H), 6.47 (s, 1H), 5.26 (s,2H), 4.91 (s, 2H), 2.45 (s, 3H).

Step 3: Methyl2-[7-(4-fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]acetate

To a solution of3-(chloromethyl)-7-(4-fluorophenoxymethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(200 mg, 0.59 mmol) in methanol (5 mL) was added1,1′-bis(diphenylphosphino)ferrocenepalladium dichloride (60 mg, 0.08mmol), potassium carbonate (163 mg, 1.18 mmol). The reaction mixture wasstirred for 3 h at 25° C. under carbon monoxide (5 atm) atmosphere.After filtration, the filtrate was concentrated in vacuo. The residuewas purified by chromatography with dichloromethane/ethyl acetate (50/1)to afford methyl2-[7-(4-fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]acetateas a white solid (120 mg, 56%). LCMS (ESI): M+H⁺=363.2; ¹H NMR (400 MHz,CDCl₃) δ 7.01-6.95 (m, 2H), 6.91-6.86 (m, 2H), 6.37 (s, 1H), 4.89 (s,2H), 4.19 (s, 2H), 3.75 (s, 3H), 2.33 (s, 3H).

Step 4:2-[7-(4-Fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]-N-methylacetamide

Methyl2-[7-(4-fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]acetate(70 mg, 0.19 mmol) and a methylamine in ethanol solution (30%, 5 mL)were added to a 25-mL round-bottom flask. The resulting solution wasstirred for 30 min at 40° C. and then concentrated in vacuo. The residuewas purified by chromatography with dichloromethane/ethyl acetate (10/1)to afford2-[7-(4-fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]-N-methylacetamideas a white solid (38 mg, 54%). LCMS (ESI): M+H⁺=362.0; ¹H NMR (300 MHz,CDCl₃) δ 7.02-6.87 (m, 5H), 6.44 (s, 1H), 4.92 (s, 2H), 4.12 (s, 2H),2.78-2.76 (m, 3H), 2.51 (s, 3H).

The following examples were prepared using methods analogous to thosedescribed above:

LCMS No. Structure/Name (M + H) ¹H NMR 2.7 

359.0 ¹H NMR (300 MHz, CDCl₃) δ 7.02-6.87 (m, 4H), 6.50 (s, 1H), 4.94(s, 2H), 2.38 (s, 3H), 2.19- 2.10 (m, 1H), 1.38-1.31 (m, 2H), 1.17-1.11(m, 2H) 2.8 

348.0 ¹H NMR (300 MHz, CDCl₃) δ 7.07-6.98 (m, 4H), 6.38 (s, 1H), 4.98(s, 2H), 2.36 (s, 2H), 2.29 (s, 1H), 2.18 (s, 1H), 2.10 (s, 2H) 2.9 

375.0 ¹H NMR (300 MHz, DMSO-d₆) δ 7.17-7.13 (m, 4H), 6.28 (s, 1H), 6.04(s, 1H), 5.69 (s, 1H), 5.16-5.12 (m, 1H), 5.00 (s, 2H), 4.35-4.25 (m,2H), 2.30 (s, 3H) 2.10

389.0 ¹H NMR (300 MHz, CDCl₃) δ 7.95 (s, 1H), 7.03-6.96 (m, 2H),6.93-6.87 (m, 2H), 6.66 (s, 1H), 5.35-5.33 (m, 1H), 4.96 (s, 2H), 2.50(s, 3H) 2.11

386.8 ¹HNMR (300 MHz, CDCl₃) δ 7.03-6.96 (m, 2H), 6.93-6.87 (m, 2H),6.59 (s, 1H), 4.95 (s, 2H), 2.44 (s, 3H)

Method 3 Example 3.1:2-cyclopropyl-N-ethyl-7-((4-fluorophenoxy)methyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

Step 1:7-(chloromethyl)-2-cyclopropyl-N-ethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

To a solution of 2-amino-5-cyclopropyl-N-ethylthiazole-4-carboxamide(2.53 g, 12.8 mmol) in polyphosphoric acid (16.0 g) was added ethyl4-chloro-3-oxobutanoate (4.20 g, 25.5 mmol). The resulting solution wasstirred for 1 h at 110° C. The reaction was then quenched by water (80mL) and the pH value of the solution was adjusted to pH 7 with a sodiumhydroxide solution (1 mol/L). The reaction mixture was extracted withdichloromethane (3×50 mL), washed with brine (30 mL), dried overanhydrous magnesium sulfate and concentrated in vacuo. The residue waspurified by chromatography with dichloromethane/ethyl acetate (5/1) toafford7-(chloromethyl)-2-cyclopropyl-N-ethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamideas a brown solid (905 mg, 24%). LCMS (ESI): M+H⁺=312.0.

Step 2:2-cyclopropyl-N-ethyl-7-((4-fluorophenoxy)methyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

A solution of7-(chloromethyl)-2-cyclopropyl-N-ethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide(100 mg, 0.32 mmol) in acetonitrile (10 mL) was treated with potassiumiodide (27.0 mg, 0.16 mmol), potassium carbonate (88.0 mg, 0.64 mmol)and 4-fluorophenol (72.0 mg, 0.64 mmol). The reaction mixture was thenstirred overnight at 80° C. After cooling down to room temperature, thereaction mixture was concentrated in vacuo. The residue was purified bychromatography with dichloromethane/methanol (50/1) to afford2-cyclopropyl-N-ethyl-7-(4-fluorophenoxymethyl)-5-oxo-5H-[1,3]Thiazolo[3,2-a]pyrimidine-3-carboxamideas a white solid (36.4 mg, 29%). LCMS (ESI): M+H⁺=388.0; ¹H NMR (300MHz, CDCl₃) δ 7.00-6.95 (m, 2H), 6.90-6.84 (m, 2H), 6.44 (s, 1H), 5.91(s, 1H), 4.90 (s, 2H), 3.57-3.53 (m, 2H), 2.19-2.09 (m, 1H), 1.32-1.27(m, 3H), 1.22-1.08 (m, 2H), 0.90-0.83 (m, 2H).

The following examples were prepared in a manner similar to Example 3.1:

LCMS No. Structure/Name (M + H) ¹H NMR 3.2

401.9  ¹H NMR (300 MHz, CDCl₃) δ 7.02-6.95 (m, 2H), 6.92-6.85 (m, 2H),6.53 (s, 1H), 5.89 (bs, 1H), 4.92 (s, 2H), 3.10-3.06 (m, 3H) 3.3

374.0  ¹H NMR (300 MHz, CDCl₃) δ 7.02-6.91 (m, 2H), 6.90-6.85 (m, 2H),6.42 (s, 1H), 6.11 (s, 1H), 4.89 (s, 2H), 3.07 (s, 3H), 2.21-2.12 (m,1H), 1.29- 1.08 (m, 2H), 0.92-0.81 (m, 2H). 3.4

415.95 ¹H NMR (300 MHz, CDCl₃) δ 7.02-6.96 (m, 2H), 6.91-6.85 (m, 2H),6.53 (s, 1H), 5.87 (br, 1H), 4.92 (s, 2H), 3.60-3.51 (m, 2H), 1.31-1.27(m, 3H) 3.5

334.0  ¹H NMR (300 MHz, CDCl₃) δ 8.07 (s, 1H), 7.03-6.96 (m, 2H), 6.94-6.88 (m, 2H), 6.59 (s, 1H), 4.96 (s, 2H), 2.99 (s, 3H)

The following example was prepared using methods analogous to thosedescribed above.

LCMS No. Structure/Name (M + H) ¹H NMR 3.6

363.15 ¹H NMR (300 MHz, CD₃OD) δ 7.99-7.98 (m, 1H), 7.61-7.54 (m, 1H),7.00-6.96 (m, 1H), 6.32 (s, 1H), 5.27 (s, 2H), 3.45-3.38 (m, 2H), 2.42(s, 3H), 1.26- 1.22 (m, 3H)

Method 4 Example 4.1:7-(4-Fluorophenoxymethyl)-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneExample 4.2:7-(4-Fluorophenoxymethyl)-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(Enantiomer 1) Example 4.3:7-(4-Fluorophenoxymethyl)-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(Enantiomer 2)

Step 1:tert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)methoxy)silane

Diethylzinc (1.0 M in hexane) (200 mL, 200 mmol) was added to freshlydistilled dichloromethane (200 mL) under nitrogen. Then a solution oftrifluoroacetic acid (15.4 mL, 200 mmol) in dichloromethane (100 mL) wasadded drop-wise at 0° C. Upon stirring for 30 min, a solution ofdiiodomethane (16.1 mL, 200 mmol) in dichloromethane (100 mL) was addedat 0° C. After an additional 30 min of stirring, a solution of(E)-tert-butyldimethyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyloxy)silane(30.0 g, 100 mmol) in dichloromethane (100 mL) was added at 0° C. Theresulting solution was stirred 2 h at room temperature and was thenquenched with water. The reaction was extracted with dichloromethane(1000 mL×2), washed with brine, and the organic layer was then driedover anhydrous sodium sulfate and concentrated to affordtert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)methoxy)silaneas a colorless oil (30 g, 96%). ¹H NMR (300 MHz, CDCl₃) δ 3.58-3.53 (m,1H), 3.44-3.38 (m, 1H), 1.17 (s, 12H), 0.87 (s, 9H), 0.66-0.63 (m, 1H),0.54-0.49 (m, 1H), 0.06 (s, 6H), −0.35 to −0.25 (m, 2H).

Step 2: Potassium trans-2-(hydroxymethyl)cyclopropyltrifluoroborate

To a solution oftert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)methoxy)silane(30.0 g, 100 mmol) in methanol (300 mL) was added a solution ofpotassium difluoride (32.0 g, 400 mmol) in water (100 mL) dropwise at 0°C. After stirring 1.5 h at room temperature, the reaction mixture wasconcentrated under reduce pressure. The resulting solid was suspended inacetone (1 L) and was refluxed 20 min. The heterogeneous mixture wasthen filtered to remove potassium difluoride and the filtrate wasconcentrated. The extraction was repeated for the filtered solid. Thecombined filtrates were concentrated and dissolved in minimal acetonefollowed by the slow addition of ethyl ether until the solution becomecloudy. The mixture was filtered and the solid was collected to providepotassium trans-2-(hydroxymethyl)cyclopropyltrifluoroborate (7.00 g,40%). ¹H NMR (300 MHz, CDCl₃) δ 4.01-3.97 (m, 1H), 3.44-3.37 (m, 1H),2.83-2.75 (m, 1H), 0.58-0.48 (m, 1H), 0.01 to −0.03 (m, 1H), −0.21 to−0.25 (m, 1H), −0.94 to −0.97 (m, 1H).

Step 3: 2-(5-methylthiazol-2-yl)isoindoline-1,3-dione

5-Methylthiazol-2-amine (200 g, 1.75 mol) and phthalic acid anhydride(272.4 g, 1.84 mol) were suspended in dioxane (2.5 L) and heated at 110°C. overnight. TLC (DCM/MeOH=20:1) showed the reaction was complete. Themixture was concentrated, and the residue was purified via columnchromatography on silica gel (DCM/MeOH=50:1˜20:1) to give2-(5-methylthiazol-2-yl)isoindoline-1,3-dione (240 g, 56%) as anoff-white solid. LCMS (ESI): M+H⁺=245.1; ¹H NMR (400 MHz, CDCl₃) δ8.01-7.99 (m, 2H), 7.84-7.82 (m, 2H), 7.46 (s, 1H), 2.51 (s, 3H).

Step 4: 2-(4-bromo-5-methylthiazol-2-yl)isoindoline-1,3-dione

To a mixture of 2-(5-methylthiazol-2-yl)isoindoline-1,3-dione (250 g,0.819 mol) in THF (2 L) was added N-bromosuccinimide (330 g, 1.85 mol)portionwise at room temperature. Then the mixture was stirred overnightat 30° C. LCMS showed the reaction was complete. The mixture was dilutedwith water and ethyl acetate. The mixture was filtered and the filtercake was dried to give2-(4-bromo-5-methylthiazol-2-yl)isoindoline-1,3-dione (210 g, 75%) as ayellow solid. LCMS (ESI): M+H⁺=323.1, 325.1; ¹H NMR (400 MHz, DMSO-d₆) δ8.03-8.00 (m, 2H), 7.95-7.93 (s, 2H), 2.41 (s, 3H).

Step 5: 4-bromo-5-methylthiazol-2-amine

A mixture of 2-(4-bromo-5-methylthiazol-2-yl)isoindoline-1,3-dione (152g, 0.471 mol) and hydrazine monohydrate (29.5 g, 0.495 mol) in EtOH (1.5L) was stirred overnight at 20° C. TLC (100% DCM) showed the reactionwas complete. The mixture was then concentrated and the residue waspurified via column chromatography on silica (100% DCM) to give4-bromo-5-methylthiazol-2-amine (67 g, 73%) as a white solid. LCMS(ESI): M+H⁺=193.1; ¹H NMR (400 MHz, CDCl₃) δ 8.52 (br, 1H), 5.11 (br,1H), 2.23 (s, 1H).

Step 6:3-bromo-7-(chloromethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

A mixture of 4-bromo-5-methylthiazol-2-amine (60 g, 0.31 mol) and4-chloro-3-oxo-butanoate (62 g, 0.37 mol) in PPA (500 g) was stirred for2 h at 110° C. LCMS showed the reaction was complete. The aqueous layerwas extracted with DCM (300 mL×3). The combined organic layers werewashed with water (200 mL×3) and brine (200 mL), dried over Na₂SO₄ andconcentrated. The residue was purified via chromatography on silica gel(DCM/MeOH=100:1˜50:1) to give3-bromo-7-(chloromethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (50g, 55%) as a brown solid. LCMS (ESI): M+H⁺=293.1, 295.1; ¹H NMR (400MHz, CDCl₃) δ 6.39 (s, 1H), 4.39 (s, 2H), 2.38 (s, 3H).

Step 7:3-bromo-7-((4-fluorophenoxy)methyl)-2-methyl-5H-thiazolo[3,2-c]pyrimidin-5-one

To a solution of3-bromo-7-(chloromethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (20g, 0.068 mmol) in acetonitrile (300 ml) was added 4-fluorophenol (9.20g, 0.082 mmol), potassium iodide (5.68 g, 0.034 mmol), and potassiumcarbonate (26.1 g, 0.136 mmol). The mixture was stirred for 3 h at 80°C. and then cooled down room temperature. After filtration andconcentration, the residue was purified by chromatography by ethylacetate/petroleum ether (1/1) to afford3-bromo-7-((4-fluorophenoxy)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(20 g, 80%) as a yellow solid. LCMS (ESI): M+H⁺=369.1, 371.1; ¹H NMR(300 MHz, CDCl₃) δ 7.01-6.95 (m, 2H), 6.92-6.86 (m, 2H), 6.44 (s, 1H),4.88 (s, 2H), 2.36 (s, 3H).

Step 8:7-(4-Fluorophenoxymethyl)-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneand7-(4-Fluorophenoxymethyl)-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(Enantiomer 1 and Enantiomer 2)

3-Bromo-7-((4-fluorophenoxy)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(500 mg, 1.36 mmol), sodium carbonate (430 mg, 4.07 mmol),1,1′-bis(diphenylphosphino)-ferrocenepalladiumdichloride (200 mg, 0.27mmol), potassium organotrifluoroborates (500 mg, 2.80 mmol), 1,4-dioxane(12 mL) and water (3 mL) were placed in a 30-mL sealed tube. Thereaction was stirred at 120° C. for 1.5 h under microwave irradiation.The reaction was then extracted with dichloromethane, washed with brine,dried over sodium sulfate and concentrated in vacuo. The residue waspurified by chromatography with dichloromethane/ethyl acetate (2/1) toafford7-(4-fluorophenoxymethyl)-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(Example 4.1) as a light yellow solid (3.00 g, 30%). LCMS (ESI):M+H⁺=361.1; 1HNMR (300 MHz, CDCl₃) δ 7.04-6.98 (m, 2H), 6.93-6.89 (m,2H), 6.48 (s, 1H), 4.92 (s, 2H), 4.09-4.05 (m, 1H), 3.16-3.09 (m, 1H),2.41 (s, 3H), 2.36-2.28 (m, 1H), 1.31-1.28 (m, 1H), 1.07-1.00 (m, 2H).

Example 4.1 was purified by Chiral-Prep-HPLC with the followingconditions (Prep-SFC80): Column, Chiralpak IC, 2*25 cm, 5 um; mobilephase, CO₂ and EtOH (0.2% DEA) (hold 65% CO₂ in 13 mins); Detector, UV220 nm to afford two enantiomers.

Peak (9.93 min): Enantiomer 1 (1.09 g, 10%). LCMS (ESI): M+H⁺=361.0; 1HNMR (300 MHz, CDCl₃) δ 7.03-6.87 (m, 4H), 6.46 (s, 1H), 4.91 (s, 2H),4.08-4.03 (m, 1H), 3.16-3.08 (m, 1H), 2.40 (s, 3H), 2.31-2.23 (m, 1H),1.32-1.26 (m, 1H), 1.07-0.96 (m, 2H).

Peak (11.06 min): Enantiomer 2 (0.96 g, 10%). LCMS (ESI): M+H⁺=361.0; ¹HNMR (300 MHz, CDCl₃) δ 7.02-6.89 (m, 4H), 6.47 (s, 1H), 4.91 (s, 2H),4.08-4.03 (m, 1H), 3.16-3.09 (m, 1H), 2.40 (s, 3H), 2.30-2.28 (m, 1H),1.30-1.25 (m, 1H), 1.07-1.01 (m, 2H).

The following examples were prepared in a manner similar to Example 4.1,4.2, and 4.3:

LCMS No. Structure/Name (M + H) ¹H NMR 4.4 

361.0  ¹H NMR (300 MHz, CDCl₃) δ 7.26-7.21 (m, 1H), 6.76-6.64 (m, 3H),6.45 (s, 1H), 4.93 (s, 2H), 4.08-4.03 (m, 1H), 3.16-3.09 (m, 1H), 2.39(s, 3H), 2.32-2.26 (m, 1H), 1.31-1.23 (m, 1H), 1.07-0.97 (m, 2H) 4.5 

369.1  ¹H NMR (300 MHz, CDCl₃) δ 9.26 (s, 1H), 8.69 (s, 2H), 7.01- 6.87(m, 4H), 6.40 (s, 1H), 4.94 (s, 2H), 2.29 (s, 3H) 4.6 

379.10 ¹H NMR (300 MHz, CDCl₃) δ 6.95-6.86 (m, 2H), 6.81-6.74 (m, 1H),6.50 (s, 1H), 4.96 (s, 2H), 4.08-4.03 (m, 2H), 3.15-3.08 (m, 1H), 2.41(s, 3H), 2.40-2.27 (m, 1H), 1.30-1.25 (m, 1H), 1.07- 0.96 (m, 2H) 4.7 

379.25 ¹H NMR (300 MHz, CDCl₃) δ 7.14-7.05 (m, 1H), 6.82-6.75 (m, 1H),6.68-6.64 (m, 1H), 6.43 (s, 1H), 4.90 (s, 1H), 4.10-4.05 (m, 1H),3.16-3.09 (m, 1H), 2.41 (s, 3H), 2.37-2.29 (m, 1H), 1.34- 1.27 (m, 2H),1.08-0.98 (m, 2H) 4.8 

377.0  ¹H NMR (300 MHz, CDCl₃) δ 7.26-7.24 (m, 2H), 6.91-6.87 (m, 2H),6.45 (s, 1H), 4.97 (s, 2H), 4.11-4.03 (m, 1H), 3.16-3.09 (m, 1H), 2.43(s, 3H), 2.40-2.28 (m, 1H), 1.27-1.19 (m, 1H), 1.07- 1.01 (m, 2H) 4.9 

362.0  ¹H NMR (300 MHz, CD₃OD) δ 8.02-8.01 (m, 1H), 7.60-7.59 (m, 1H),7.01-6.97 (m, 1H), 6.27 (s, 1H), 5.25 (s, 2H), 3.64-3.60 (m, 2H), 2.45(s, 3H), 2.23-2.17 (m, 1H), 1.41-1.32 (m, 1H), 1.07- 1.01 (m, 2H) 4.10

411.0  ¹H NMR (300 MHz, CDCl₃) δ 7.60-7.56 (m, 2H), 7.04-7.01 (m, 2H),6.45 (s, 1H), 5.04 (s, 2H), 4.07-4.02 (m, 1H), 3.17-3.13 (m, 1H), 2.41(s, 3H), 2.34-2.27 (m, 1H), 1.30-1.26 (m, 1H), 1.08- 1.01 (m, 2H). 4.11

358.0  ¹H NMR (300 MHz, CDCl₃) δ 7.85 (s, 1H), 7.34 (s, 1H), 7.01- 6.86(m, 4H), 6.42 (s, 1H), 4.93 (s, 2H), 2.37 (s, 3H). 4.12

361.0  ¹HNMR (300 MHz, CDCl₃) δ 7.17-6.96 (m, 4H), 6.57 (s, 1H), 5.08(s, 2H), 4.09-4.08 (m, 1H), 3.20-3.15 (m, 1H), 2.44 (s, 3H), 2.32-2.17(m, 1H), 1.31-1.28 (m, 1H), 1.09-1.02 (m, 2H) 4.13

368.0  ¹H NMR (300 MHz, DMSO-d₆) δ 7.82-7.79 (m, 2H), 7.23-7.20 (m, 2H),6.22 (s, 1H), 5.07 (s, 2H), 4.59-4.55 (m, 1H), 3.48- 3.44 (m, 2H), 2.37(s, 3H), 2.05- 2.01 (m, 1H), 1.33-1.25 (m, 1H), 0.89-0.86 (m, 2H) 4.14

347.1  ¹H NMR (400 MHz, DMSO-d₆) δ 7.18-7.10 (m, 2H), 7.10-7.03 (m, 2H),7.02 (s, 1H), 6.23 (s, 1H), 4.97 (s, 2H), 4.43 (dd, J = 6.6, 4.6 Hz,1H), 3.55-3.36 (m, 2H), 2.63-2.54 (m, 1H), 1.41- 1.26 (m, 1H), 1.01 (dt,J = 8.5, 5.2 Hz, 1H), 0.87 (dt, J = 8.4, 5.2 Hz, 1H). 4.15

357.1  ¹H NMR (400 MHz, DMSO-d₆) δ 12.97 (s, 1H), 7.78 (s, 1H),7.19-7.09 (m, 2H), 7.09-6.97 (m, 2H), 6.47-6.26 (m, 1H), 6.16 (s, 1H),4.99 (s, 2H), 2.20 (s, 3H). 4.16

358.1  ¹H NMR (400 MHz, DMSO-d₆) δ 9.64 (s, 1H), 7.18-7.08 (m, 2H),7.08-7.00 (m, 2H), 6.19 (s, 1H), 5.01 (s, 2H), 2.22 (d, J = 13.2 Hz,3H). 4.17

331.1  ¹H NMR (400 MHz, DMSO-d₆) δ 7.20-7.09 (m, 2H), 7.09-6.96 (m, 2H),6.18 (s, 1H), 4.94 (s, 2H), 2.35 (d, J = 1.5 Hz, 3H), 2.16 (tdd, J =8.5, 5.1, 1.9 Hz, 1H), 0.99-0.87 (m, 2H), 0.75- 0.58 (m, 2H).

Example 4.18:cis-2-[7-(4-Fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropane-1-carbonitrile

and

Example 4.18Atrans-2-[7-(4-Fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropane-1-carbonitrile

Step 1: Ethyl2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropanecarboxylate

To a solution of 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.0g, 4.38 mmol) and palladium acetate (166 mg, 0.44 mmol) in ether (50 mL)was added ethyl 2-diazoacetate (6.60 g, 5.47 mmol) in ether (20 mL)dropwise for 10 min at room temperature. Palladium acetate (166 mg, 0.44mmol) and ethyl 2-diazoacetate (6.60 g, 5.47 mmol) in ether (20 mL) wereagain added dropwise for another 10 min. The resulting solution was thenstirred for 1 h at room temperature. After filtration through activealuminum oxide, the filtrate was concentrated in vacuo to afford ethyl2-(tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropane-1-carboxylate asyellow oil (24.0 g). The crude product was used in the next step withoutfurther purification.

Step 2: Ethyl2-[7-(4-fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropane-1-carboxylate

To a solution of3-bromo-7-(4-fluorophenoxymethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(from Example 4.1, Step 7) (500 mg, 1.35 mmol), ethyl2-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)cyclopropane-1-carboxylate(2.25 g, 6.37 mmol) and potassium carbonate (697 mg, 5.20 mmol) in 5:1acetonitrile/water (12 mL) was added1,1′-bis(diphenylphosphino)ferrocenepalladium dichloride (54.7 mg, 0.06mmol). The resulting solution was stirred for 1 h at 120° C. in a 20-mLmicrowave tube. The process was then scaled up to 5 g (10 batches) usingthe same method. After concentration in vacuo, the residue was purifiedby chromatography with ethyl acetate/petroleum ether (1/2) to affordethyl2-[7-(4-fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropane-1-carboxylateas a red oil (1.50 g, 28%). LCMS (ESI): M+H⁺=403.0.

Step 3:2-[7-(4-Fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropane-1-carboxylicacid

To a solution of ethyl2-[7-(4-fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropane-1-carboxylate(1.50 g, 3.75 mmol) in tetrahydrofuran/water (100/10 mL) was addedlithium hydroxide (850 mg, 35.5 mmol) and the solution was stirredovernight at room temperature. The pH value of the solution was adjustedto 4-5 with hydrogen chloride (1 mol/L). The resulting solution wasextracted with ethyl acetate (2×200 mL) and dried over anhydrousmagnesium sulfate. After filtration, the filtrate was concentrated invacuo to afford2-(7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)cyclopropane-1-carboxylicacid as a yellow oil (800 mg, 57%). LCMS (ESI): M+H⁺=375.0.

Step 4:2-(7-((4-fluorophenoxy)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)cyclopropanecarboxamide

To a solution of2-[7-(4-fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropane-1-carboxylicacid (800 mg, 2.25 mmol), triethylamine (325 mg, 3.25 mmol,) intetrahydrofuran (100 mL) was added propan-2-ylchloroformate (325 mg,2.75 mmol). The solution was stirred for 20 min at room temperature.Then ammonium hydroxide (10 mL, 2.60 mmol) was added and the solutionwas stirred for an additional 20 min at room temperature. The resultingsolution was extracted with ethyl acetate (2×100 mL), washed with brine,dried over anhydrous magnesium sulfate and concentrated in vacuo. Theresidue was purified by chromatography with 3% methanol indichloromethane to afford2-(7-((4-fluorophenoxy)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)cyclopropanecarboxamideas a white solid (500 mg, 62%).

Step 5:2-(7-((4-fluorophenoxy)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)cyclopropanecarbonitrile

To a solution of2-(7-((4-fluorophenoxy)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)cyclopropanecarboxamide(500 mg, 1.20 mmol) in dichloromethane (100 mL) was added1,8-diazabicyclo[5.4.0]undec-7-ene (100 mL) and ethyl dichlorophosphate(50 mL). After stirring for 30 min at room temperature, the reaction wasquenched with water (50 mL) and extracted with dichloromethane (3×20 mL)and the combined organic layer was washed with brine, dried overanhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by preparative HPLC with the following conditions:(1#-Pre-HPLC-005(Waters)): Column, SunFire Prep C₁₈ OBD Column, 5 um,19*150 mm; mobile phase, water with 10 mmol NH₄HCO₃ and CH₃CN (50.0%CH₃CN up to 82.0% in 10 min, down to 50.0% in 2 min); Detector, UV254/220 nm to afford the cis (Example 4.18; 200 mg, 42%) and trans(Example 4.18A; 60 mg, 12%) isomers.

Example 4.18

LCMS (ESI): M+H⁺=356.2; ¹H NMR (300 MHz, CD₃OD) δ 7.07-7.01 (m, 4H),6.40 (s, 1H), 4.97 (s, 2H), 3.10-2.92 (m, 1H), 2.42 (s, 3H), 2.05-1.96(m, 1H), 1.84-1.77 (m, 1H), 1.62-1.55 (m, 1H).

Examples 4.19 and 4.20

The racemic cis isomer (Ex. 4.18) was purified by Chiral-Prep-HPLC withthe following conditions (Prep-HPLC-032): Column, Chiralpak IA, 2*25 cm,5 um; mobile phase, Hex (1% TEA)/EtOH (hold 50.0% EtOH in 12 mins),flow, 1.0 mL/min; Detector, UV 254 nm to afford two enantiomers.

Example 4.19 (Cis Enantiomer 1)

Obtained as a white solid (58.6 mg, 16%). Chrial-Prep-HPLC retentiontime, 6.48 min; LCMS(ESI): M+H⁺=356.2; ¹H NMR (400 MHz, CDCl₃) δ7.03-7.00 (m, 2H), 6.92-6.89 (m, 2H), 6.46 (s, 1H), 4.90 (s, 2H),3.02-3.01 (m, 1H), 2.42 (s, 3H), 1.88-1.83 (m, 1H), 1.74-1.69 (m, 1H),1.48-1.42 (m, 1H).

Example 4.20 (Cis Enantiomer 2)

Obtained as a white solid (67.8 mg, 19%). Chrial-Prep-HPLC retentiontime, 8.80 min; LCMS (ESI): M+H⁺=356.2; ¹H NMR (300 MHz, CD₃OD) δ7.08-7.01 (m, 4H), 6.40 (s, 1H), 4.96 (s, 2H), 2.98-2.94 (m, 1H), 2.42(s, 3H), 2.05-1.96 (m, 1H), 1.84-1.77 (m, 1H), 1.62-1.55 (m, 1H).

Examples 4.21 and 4.22

The racemic trans isomer (Ex. 4.18A) was purified by Chiral-Prep-HPLCwith the following conditions (Prep-HPLC-032): Column, Chiralpak IA,2*25 cm, 5 um; mobile phase, Hex (1% TEA)/IPA (hold 50.0% IPA in 8mins), flow, 1.0 mL/min; Detector, UV 254 nm to afford two enantiomers.

Example 4.21 (Trans Enantiomer 1)

Obtained as a white solid (7.1 mg, 1%). Chrial-Prep-HPLC retention time,2.28 min; LCMS (ESI): M+H⁺=356.2; ¹H NMR (400 MHz, CDCl₃) δ 7.05-6.91(m, 4H), 6.47 (s, 1H), 4.92 (s, 2H), 3.01-2.95 (m, 1H), 2.43 (s, 3H),2.06-2.00 (m, 1H), 1.86-1.70 (m, 1H), 1.62-1.57 (m, 1H).

Example 4.22 (Trans Enantiomer 2)

Obtained (4.4 mg, 0.5%). Chrial-Prep-HPLC retention time, 3.97 min; LCMS(ESI): M+H⁺=356.2; ¹H NMR (400 MHz, CDCl₃) δ 7.05-6.93 (m, 2H),6.95-6.91 (m, 2H), 6.47 (s, 1H), 4.92 (s, 2H), 3.01-2.95 (m, 1H), 2.43(s, 3H), 2.06-2.66 (m, 1H), 1.86-1.80 (m, 1H), 1.60-1.52 (m, 1H).

Example 4.23:7-(4-Fluorophenoxymethyl)-3-[cis-2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

Step 1:tert-Butyldimethyl[[3-(tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-yn-1-yl]oxy]silane

To a solution of tert-butyldimethyl(prop-2-yn-1-yloxy)silane (200 mg,1.17 mmol) in tetrahydrofuran (6 mL) was added 2.5 M n-butyl lithium(0.57 mL, 1.42 mmol) dropwise at −78° C. The resulting solution wasstirred for 0.5 h at −78° C. Then4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (230 mg, 1.24mmol) was added dropwise at −78° C. The resulting solution was allowedto react for an additional 4 h while the temperature was maintained at−78° C. The reaction was then quenched by hydrogen chloride in ethylether (1 mol/L). After concentration in vacuo, the residue was dilutedwith ethyl ether (20 mL) and the solids were filtered off. The filtratewas concentrated to affordtert-butyldimethyl[[3-(tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-yn-1-yl]oxy]silaneas a light yellow liquid (260 mg, 75%). ¹H NMR (300 MHz, CDCl₃) δ 4.35(s, 2H), 1.27 (s, 12H), 0.90 (s, 9H), 0.12 (s, 6H).

Step 2:tert-butyldimethyl[[(2Z)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-yl]oxy]silane

To a suspension of bis(cyclopentadienyl)zirconium chloride hydride (230mg, 0.88 mmol) in tetrahydrofuran (5 mL) was addedtert-butyldimethyl[[3-(tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-yn-1-yl]oxy]silane(260 mg, 0.88 mmol) in tetrahydrofuran (2 mL) dropwise with stirring atroom temperature. The resulting solution was stirred overnight at roomtemperature and then quenched by water (5 mL). The resulting mixture wasstirred for an additional 1 h at room temperature and was extracted withdichloromethane (2×20 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate and concentrated in vacuo.The residue was purified by silica gel chromatography with ethylacetate/petroleum ether (1/50) to affordtert-butyldimethyl[[(2Z)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-yl]oxy]silaneas a colorless oil (200 mg, 76%). ¹H NMR (400 MHz, CDCl₃) δ 6.58-6.47(m, 1H), 5.35-5.30 (m, 1H), 4.34-4.33 (m, 2H), 1.27 (s, 12H), 0.90 (s,9H), 0.12 (s, 6H).

Step 3:tert-Butyldimethyl[[2-(tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]methoxy]silane

Diethylzinc (1.0 M in hexanes) (4 mL, 4 mmol) was added to freshlydistilled dichloromethane (4 mL) under nitrogen. Then trifluoroaceticacid (0.31 mL, 4.00 mmol) in dichloromethane (2 mL) was added dropwiseat 0° C. Upon stirring for 20 min, a solution of diethylzinc in hexanes(0.32 mL, 4.00 mmol) in dichloromethane (2 mL) was added at 0° C. Afteran additional 20 min of stirring, a solution oftert-butyldimethyl[[(2Z)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-yl]oxy]silane(600 mg, 2.01 mmol) in dichloromethane (2 mL) was added at 0° C. Thenthe resulting solution was stirred 1 h at room temperature and wasquenched with water. The reaction was extracted with dichloromethane(100 mL×2), washed with brine, dried over anhydrous sodium sulfate andconcentrated to affordtert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)methoxy)silaneas a colorless oil (600 mg, 96%).

Step 4: Potassium cis-2-(hydroxymethyl)cyclopropyltrifluoroborate

To a solution oftert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)methoxy)silane(600 mg, 2.00 mmol) in methanol (4 mL) was added potassium difluoride(630 mg, 8 mmol) in water (2 mL) drop wise at 0° C. After stirred 1.5 hat room temperature, the reaction mixture was concentrated in vacuo. Theresulting solid was suspended in acetone (20 mL) and refluxed 20 min.The heterogeneous mixture was then filtered to remove potassiumdifluoride and the filtrate was concentrated. The extraction process wasrepeated for the filtered solid. The combined filtrates wereconcentrated and dissolved in minimal acetone followed by the slowaddition of ethyl ether until the solution become cloudy. The solidswere collected by filtration and dried to afford the title compound as awhite solid (150 mg, 43%).

Step 5:7-(4-Fluorophenoxymethyl)-3-[cis-2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

3-Bromo-7-(4-fluorophenoxymethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(from Example 4.1, Step 7) (100 mg, 0.27 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (20.0 mg, 0.03mmol), sodium carbonate (60.0 mg, 0.57 mmol), potassiumcis-2-(hydroxymethyl)cyclopropyltrifluoroborate (100 mg, 0.56 mmol),acetonitrile (3 mL) and water (0.5 mL) were placed in a 10-mL sealedtube. The final reaction mixture was heated in a microwave reactor for1.5 h at 120° C. The mixture was extracted with dichloromethane (20 mL),washed with brine (10 mL), dried over anhydrous sodium sulfate andconcentrated. The residue was purified by chromatography with ethylacetate/petroleum ether (2:1) to give7-(4-fluorophenoxymethyl)-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas a white solid (23.5 mg, 24%). LCMS (ESI): M+H⁺=361.0; ¹H NMR (300MHz, CDCl₃) δ 7.02-6.88 (m, 4H), 6.45 (s, 1H), 4.90 (s, 2H), 3.69-3.64(m, 1H), 3.17-3.11 (m, 1H), 2.55-2.47 (m, 1H), 2.42 (s, 3H), 1.68-1.59(m, 1H), 1.47-1.40 (m, 1H), 0.83-0.77 (m, 1H).

Example 4.24:trans-7-(4-Fluorophenoxymethyl)-2-methyl-3-[2-(trifluoromethyl)cyclopropyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

Step 1: 2-Diazo-1,1,1-trifluoroethane

To a solution of 2,2,2-trifluoroethan-1-amine hydrochloride (3.24 g,23.9 mmol) in water (5 mL) and ethyl ether (10 mL) was added dropwise asolution of sodium nitrite (1.84 g, 26.7 mmol) in water (2 mL). Theresulting solution was stirred for 3 h at room temperature. The solidswere filtered out to afford 2-diazo-1,1,1-trifluoroethane as a lightyellow liquid (1.32 g, 51%). No LCMS signal.

Step 2:4,4,5,5-Tetramethyl-2-[2-(trifluoromethyl)cyclopropyl]-1,3,2-dioxaborolane

To a solution of 2-diazo-1,1,1-trifluoroethane (530 mg, 4.82 mmol) inether (100 mL) was added palladium acetate (50.0 mg, 0.22 mmol). Then2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.66 g, 4.29 mmol)and palladium acetate (50.0 mg, 0.22 mmol) were added with stirring over20 min. After the resulting solution was stirred for 1 h at roomtemperature, the solids were filtered off. The resulting solution wasconcentrated in vacuo to afford4,4,5,5-tetramethyl-2-[2-(trifluoromethyl)cyclopropyl]-1,3,2-dioxaborolaneas dark green oil (580 mg, 51%).

Step 3:trans-7-(4-Fluorophenoxymethyl)-2-methyl-3-[2-(trifluoromethyl)cyclopropyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a solution of4,4,5,5-tetramethyl-2-[2-(trifluoromethyl)cyclopropyl]-1,3,2-dioxaborolane(384 mg, 1.63 mmol) in acetonitrile (3 mL) and water (1 mL) was added3-bromo-7-(4-fluorophenoxymethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(300 mg, 0.81 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladiumdichloride (59 mg, 0.08 mmol) and sodium carbonate (12 mg). Theresulting solution was stirred for 1.5 h at 120° C. under nitrogenatmosphere and then diluted with water (5 mL). After extraction withdichloromethane (3×30 mL), the combined organic layers were washed withbrine, dried over anhydrous sodium sulfate and concentrated in vacuo.The crude product was purified by Prep-HPLC (Conditions:(Prep-HPLC-005): Column, Xbridge Prep C₁₈ OBD Column, 5 um, 19×150 mm;mobile phase, water with 10 mmol ammonium dicarbonate and acetonitrile(35.0% acetonitrile up to 59.0% in 10 min); Detector, UV 254/220 nm) toafford7-(4-fluorophenoxymethyl)-2-methyl-3-[2-(trifluoromethyl)cyclopropyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas a white solid (4.40 mg, 1%). LCMS (ESI): M+H⁺=399.2; ¹H NMR (300 MHz,CDCl₃) δ 7.02-6.96 (m, 2H), 6.92-6.87 (m, 1H), 6.42 (s, 1H), 4.90 (s,2H), 2.81-2.76 (m, 1H), 2.42 (s, 3H), 1.98-1.87 (m, 1H), 1.55-1.48 (m,1H), 1.18-1.10 (m, 1H).

Example 4.25:7-(4-Fluorophenoxymethyl)-2-methyl-3-(2-methylcyclopropyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

Step 1: 4,4,5,5-Tetramethyl-2-(2-methylcyclopropyl)-1,3,2-dioxaborolane

To a solution of 1 M diethylzinc in hexanes (0.36 mL, 0.36 mmol) indichloromethane (4 mL) was added a solution of trifluoroacetic acid (408mg, 3.58 mmol) in dichloromethane (4.0 mL), followed by a solution ofdiiodomethane (957 mg, 3.57 mmol) in dichloromethane (4.0 mL) undernitrogen and the reaction solution was stirred for 40 min at 0° C. Thena solution of4,4,5,5-tetramethyl-2-[(1E)-prop-1-en-1-yl]-1,3,2-dioxaborolane (300 mg,1.79 mmol) in dichloromethane (2 mL) was added and the reaction mixturewas stirred for an additional 50 min at room temperature. The reactionwas quenched by a saturated ammonium chloride solution (10 mL),extracted with petroleum ether (3×20 mL), washed with brine, dried withanhydrous sodium sulfate and concentrated in vacuo to afford4,4,5,5-tetramethyl-2-(2-methylcyclopropyl)-1,3,2-dioxaborolane as ayellow solid (300 mg). The crude product was used in next step withoutfurther purification. LCMS (ESI): M+H⁺=376.1; ¹H NMR (300 MHz, CD₃OD) δ1.21 (s, 12H), 1.08-1.06 (m, 3H), 0.95-0.91 (m, 1H), 0.69-0.65 (m, 1H),0.38-0.32 (m, 1H), −0.42 to −0.47 (m, 1H).

Step 2:7-(4-Fluorophenoxymethyl)-2-methyl-3-(2-methylcyclopropyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-bromo-7-(4-fluorophenoxymethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(from Example 4.1, Step 7) (100 mg, 0.27 mmol) in acetonitrile/water(1.5/0.5 mL) was added4,4,5,5-tetramethyl-2-(2-methylcyclopropyl)-1,3,2-dioxaborolane (100 mg,0.55 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium dichloride(20.3 mg, 0.03 mmol) and sodium carbonate (57.0 mg, 0.54 mmol). Thereaction mixture was heated under microwave yridine ra for 90 min at120° C. The reaction was then concentrated under vacuum and theresulting residue was purified by chromatography withdichloromethane/methanol (50/1) to afford7-(4-fluorophenoxymethyl)-2-methyl-3-(2-methylcyclopropyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas an off-white solid (17.6 mg, 18%). LCMS (ESI): M+H⁺=345.1; ¹H NMR(300 MHz, CDCl₃) δ 7.01-6.95 (m, 2H), 6.91-6.86 (m, 2H), 6.38 (s, 1H),4.88 (s, 2H), 2.36 (s, 3H), 1.94-1.90 (m, 1H), 1.24-1.22 (m, 3H),1.03-0.95 (m, 1H), 0.93-0.85 (m, 2H).

Example 4.26:trans-2-[2-[7-(4-Fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropyl]acetonitrile

Step 1:[2-[7-(4-Fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropyl]methylmethanesulfonate

To a solution of7-((3-fluorophenoxy)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(from Example 4.1, Step 8) (40.0 mg, 0.11 mmol) in dichloromethane (51mL) was added triethylamine (34.0 mg, 0.34 mmol) and methanesulfonylchloride (38.0 mg). After stirring for 1 h at room temperature, theresulting mixture was concentrated in vacuo. The residue was purified bysilica gel chromatography with 2% methanol in dichloromethane to afford[2-[7-(4-fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropyl]methylmethanesulfonate as an off-white solid (40.0 mg, 82%). LCMS (ESI):M+H⁺=439; ¹H NMR (300 MHz, CDCl₃) δ 7.03-6.89 (m, 4H), 6.41 (s, 1H),4.95 (s, 2H), 4.65-4.59 (s, 2H), 2.43 (s, 3H), 2.42-2.21 (m, 1H),1.56-1.02 (m, 3H).

Step 2:trans-2-[2-[7-(4-Fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropyl]acetonitrile

To a solution of[2-[7-(4-fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropyl]methylmethanesulfonate (50.0 mg, 0.11 mmol) in dimethyl sulfoxide (5 mL) wasadded sodium cyanide (50.0 mg). The resulting solution was stirred for 1h at 90° C. After cooling down to room temperature, the reaction mixturewas diluted with dichloromethane (10 mL), washed with water (4×5 mL),dried over anhydrous sodium sulfate and concentrated in vacuo. Theresidue was purified by Prep-HPLC (Conditions: Column, SunFire Prep C₁₈OBD Column, 5 um, 19*150 mm; mobile phase, Water with 10 mmol ammoniumbicarbonate and acetonitrile (18.0% acetonitrile up to 28.0% in 10 min,up to 95.0% in 2 min, down to 18.0% in 2 min); Detector, UV 254/220 nm)to afford2-[2-[7-(4-fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropyl]acetonitrileas a white solid (8.90 mg, 21%). LCMS (ESI): M+H⁺=370.0; ¹H NMR (300MHz, CDCl₃) δ 7.04-6.89 (m, 4H), 6.41 (s, 1H), 4.94 (s, 2H), 3.02-2.95(m, 1H), 2.56-2.45 (m, 1H), 2.42 (s, 3H), 2.06-1.96 (m, 1H), 1.32-1.23(m, 2H), 1.20-1.09 (m, 1H).

The following examples were prepared in a manner similar to Example4.26:

LCMS No. Structure/Name (M + H) ¹H NMR 4.27

375.1 ¹H NMR (300 MHz, CDCl₃) δ 7.01-6.96 (m, 2H), 6.92-6.87 (m, 2H),6.39 (s, 1H), 4.91 (s, 2H), 3.69-3.64 (m, 1H), 3.38 (s, 3H), 3.32-3.12(m, 1H), 2.42 (s, 3H), 2.19-2.16 (m, 1H), 1.45-1.34 (m, 1H), 1.13-1.07(m, 1H), 0.98-0.92 (m, 1H) 4.28

363.0 ¹H NMR (300 MHz, CDCl₃) δ 7.03-6.89 (m, 4H), 6.38 (s, 1H), 4.95(s, 2H), 4.73-4.27 (m, 2H), 2.40 (s, 3H), 2.28-2.26 (m, 1H), 1.48-1.40(m, 1H), 1.26-1.02 (m, 2H)

Example 4.29:6-fluoro-7-((4-fluorophenoxy)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

Step 1:3-bromo-7-(chloromethyl)-6-fluoro-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

Into a 30-mL sealed tube purged and maintained with nitrogen was added asolution of3-bromo-7-(chloromethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(from Example 4.1, Step 6) (500 mg, 1.70 mmol) in acetonitrile (20 mL)and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (Selectfluor®; 600 mg, 1.69 mmol). The resultingsolution was stirred for 3 h at 75° C. After cooling down to roomtemperature, the reaction mixture was concentrated in vacuo. The residuewas purified by silica gel chromatography with dichloromethane to afford3-bromo-7-(chloromethyl)-6-fluoro-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas off-white solid (250 mg, 40%). LCMS (ESI): M+H⁺=311.0, 313.0; ¹H NMR(300 MHz, CDCl₃) δ 4.55 (s, 2H), 2.41 (s, 3H).

Step 2:3-bromo-6-fluoro-7-((4-fluorophenoxy)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-bromo-7-(chloromethyl)-6-fluoro-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(300 mg, 0.96 mmol,) in acetonitrile (20 mL) was added potassium iodide(83.0 mg, 0.48 mmol), potassium carbonate (276 mg, 2.00 mmol) and4-fluorophenol (224 mg, 2.00 mmol). The reaction mixture was stirredovernight at 80° C. After cooling down to room temperature, the reactionmixture was concentrated in vacuo. The residue was purified on a silicagel column with ethyl acetate/petroleum ether (1/2) to afford3-bromo-6-fluoro-7-(4-fluorophenoxymethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas an off-white solid (50.0 mg, 11%). LCMS (ESI): M+H=387.0, 389.0.

Step 3:6-fluoro-7-((4-fluorophenoxy)methyl)-3-(2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

Into a 10-mL sealed tube purged and maintained with nitrogen was added asolution of3-bromo-6-fluoro-7-(4-fluorophenoxymethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(150 mg, 0.39 mmol) in acetonitrile/water (3/1 mL),1,1′-bis(diphenylphosphino)ferrocene-palladiumdichloride (29.0 mg, 0.04mmol), sodium carbonate (82.0 mg, 0.77 mmol) and potassiumtrans-2-(hydroxymethyl)cyclopropyltrifluoroborate (from Example 4.1,Step 2) (138 mg, 0.78 mmol). The reaction mixture was stirred for 1.5 hat 120° C. After cooling down to room temperature, the reaction mixturewas concentrated in vacuo. The residue was purified on a silica gelcolumn with dichloromethane/methanol (100/1) to afford6-fluoro-7-((4-fluorophenoxy)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-oneas off-white solid (26.1 mg, 18%). LCMS (ESI): M+H⁺=379.0; ¹H NMR (300MHz, CDCl₃) δ 6.98-6.91 (m, 4H), 5.02 (s, 2H), 4.06-4.01 (m, 1H),3.25-3.18 (m, 1H), 2.39 (s, 3H), 2.33-2.27 (m, 1H), 1.30-1.25 (m, 1H),1.08-0.99 (m, 2H).

Example 4.30:7-(4-Fluorophenoxymethyl)-3-(3-hydroxypropyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

Step 1: Ethyl (E)-ethyl3-(7-((4-fluorophenoxy)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)acrylate

To a solution of3-bromo-7-((3-fluorophenoxy)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(from Example 4.1, Step 7) (205 mg, 0.56 mmol) in acetonitrile (5 mL)was added ethyl prop-2-enoate (110 mg, 1.10 mmol), tri-tolylphosphine(25 mg), tris(dibenzylideneacetone)dipalladium (33.0 mg, 0.04 mmol) andtriethylamine (110 mg, 1.09 mmol). The reaction mixture was stirredovernight at 90° C. under a nitrogen atmosphere. After cooling down toroom temperature, the reaction mixture was concentrated in vacuo and theresidue was purified by chromatography with 3% ethyl acetate inpetroleum ether to afford ethyl (E)-ethyl3-(7-((4-fluorophenoxy)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)acrylateas an off-white solid (58.0 mg, 27%). LCMS (ESI): M+H⁺=389.0.

Step 2: ethyl3-(7-((4-fluorophenoxy)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)propanoate

To a solution of ethyl (E)-ethyl3-(7-((4-fluorophenoxy)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)acrylate(58.0 mg, 0.15 mmol) in methanol (5 mL) was added palladium on carbon(50.0 mg). The reaction mixture was stirred overnight at roomtemperature under a hydrogen atmosphere (1.5 atm). After the solids werefiltered off, the resulting mixture was concentrated in vacuo to affordethyl3-(7-((4-fluorophenoxy)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)propanoate(52.0 mg, 89%) as a white solid. LCMS (ESI): M+H⁺=391.0.

Step 3:7-(4-Fluorophenoxymethyl)-3-(3-hydroxypropyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a solution of ethyl3-[7-(4-fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]propanoate(42.0 mg, 0.11 mmol) in tetrahydrofuran (4 mL) and methanol (1 mL) wasadded lithium borohydride (23.0 mg). The reaction mixture was stirredovernight at room temperature. The reaction was then quenched with water(5 mL), extracted with dichloromethane (3×10 mL), washed with brine,dried over anhydrous sodium sulfate and concentrated in vacuo. Theresidue was purified by silica gel chromatography with 3% methanol indichloromethane to afford7-(4-Fluorophenoxymethyl)-3-(3-hydroxypropyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas a white solid (6.3 mg, 1.7%). LCMS (ESI): M+H⁺=349.1; ¹H NMR (300MHz, CDCl₃,) δ 7.02-6.91 (m, 4H), 6.46 (s, 1H), 4.92 (s, 2H), 3.70-3.65(m, 2H), 3.36-3.32 (m, 2H), 2.36 (s, 3H), 1.96-1.89 (m, 2H).

The following compounds were prepared using methods analogous to thosedescribed above:

LCMS No. Structure/Name (M + H) ¹H NMR 4.31

335.20 ¹H NMR (300 MHz, CD₃OD) δ 7.08-6.98 (m, 4H), 6.39 (s, 1H),5.01-4.96 (m, 4H), 3.41 (s, 3H), 2.49 (s, 3H). 4.32

363.1  ¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (s, 1H), 7.20-7.09 (m, 2H),7.09-6.93 (m, 2H), 6.25 (s, 1H), 4.98 (s, 2H), 4.92 (d, J = 7.8 Hz, 2H),4.63-4.45 (m, 2H), 2.26 (s, 3H). 4.33

363.0  ¹H NMR (400 MHz, DMSO-d₆) δ 7.03-6.98 (m, 2H), 6.93-6.90 (m, 2H),6.46 (s, 1H), 5.06 (s, 1H), 4.94 (s, 2H), 3.70-3.66 (m, 1H), 3.57 (m,1H), 2.46 (m, 4H), 2.08-1.92 (m, 2H), 1.36- 1.33 (m, 3H) 4.34

371.1  ¹H NMR (300 MHz, CDCl₃) δ 7.01-6.96 (m, 2H), 6.91-6.86 (m, 2H),6.45 (s, 1H), 4.90 (s, 2H), 2.57-2.50 (m, 1H), 2.39 (s, 3H), 1.28 (s,3H), 1.25-1.20 (m, 1H), 1.06 (s, 3H), 1.05-0.90 (m, 2H)

Method 5 Example 5.1:7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-pyrimidin-5-yl-thiazolo[3,2-a]pyrimidin-5-one

Step 1:3-bromo-7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

A mixture of3-bromo-7-(chloromethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(from Example 4.1, Step 6) (30 g, 0.1 mol), N-ethyl-4-fluoroaniline(18.5 g, 0.13 mol), potassium carbonate (28.2 g, 0.2 mol) and sodiumiodide (7.66 g, 0.05 mol) in acetonitrile was heated overnight at 80° C.The mixture was then cooled to room temperature, diluted with asaturated aqueous solution of ammonium chloride (300 mL) and extractedwith dichloromethane (200 mL×3). The combined organic layers were washedwith water and brine, dried over sodium sulfate and concentrated. Theresidue was triturated with dichloromethane to give3-bromo-7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(21 g, 54%) as an off-white solid.

Step 2:7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-pyrimidin-5-yl-thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-bromo-7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(50 mg, 0.13 mmol) in acetonitrile/H₂O (1.3/0.5 mL) was added(pyrimidin-5-yl) boronic acid (20.3 mg, 0.16 mmol), sodium carbonate(40.5 mg, 0.379 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (9.7 mg,0.013 mmol). The reaction mixture was heated under microwave irradiationfor 20 min at 120° C. After cooling down room temperature, the resultingmixture was concentrated in vacuo. The residue was purified by silicagel chromatography with dichloromethane/methanol (95/5) to afford7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-pyrimidin-5-yl-thiazolo[3,2-a]pyrimidin-5-one(14.8 mg, 30.0%) as an off-white solid. LCMS (ESI): M+H⁺=396.1; 1H NMR(400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.83 (s, 2H), 6.98 (t, J=8.8 Hz, 2H),6.62 (dd, J=9.2, 4.4 Hz, 2H), 5.85 (s, 1H), 4.36 (s, 2H), 3.47 (q, J=7.0Hz, 2H), 2.22 (s, 3H), 1.13 (t, J=7.0 Hz, 3H).

The following examples were prepared in a manner similar to Example 5.1:

LCMS No. Structure/Name (M + H) ¹H NMR 5.2 

382.1  ¹H NMR (300 MHz, CDCl₃) δ 9.90 (s, 1H), 9.24 (s, 2H), 6.96-6.88(m, 2H), 6.63-6.59 (m, 2H), 6.07 (s, 1H), 4.35 (s, 2H), 3.06 (s, 3H),2.25 (s, 3H). 5.3 

450.1  ¹H NMR (300 MHz, CD₃OD) δ 9.13 (s, 1H), 8.76 (s, 2H), 6.94-6.86(m, 2H), 6.79-6.75 (m, 2H), 5.97 (s, 1H), 5.54 (s, 2H), 4.25-4.16 (m,2H), 2.25 (s, 3H). 5.4 

413.8  ¹H NMR (300 MHz, CD₃OD) δ 9.17 (s, 1H), 8.81 (s, 2H), 7.07-6.97(m, 1H), 6.57-6.49 (m, 1H), 6.42-6.38 (m, 1H), 6.01 (s, 1H), 4.40 (s,2H), 3.52 (m, 2H), 2.29 (s, 3H), 1.22 (m, 3H). 5.5 

396.09 ¹H NMR (400 MHz, DMSO- d₆) δ 9.19 (s, 1H), 8.84 (s, 2H),7.15-7.12 (m, 1H), 6.47-6.39 (m, 3H), 5.84 (s, 1H), 4.42 (s, 2H),3.51-3.49 (m, 2H), 2.23 (s, 3H), 1.16-1.13 (m, 3H). 5.6 

432.0  ¹H NMR (300 MHz, CD₃OD) δ 9.20 (s, 1H), 8.89 (s, 2H), 6.90-6.77(m, 2H), 6.30-5.93 (m, 2H), 4.63 (s, 2H), 3.93- 3.83 (m, 2H), 2.29 (s,3H). 5.7 

371.0  ¹H NMR (300 MHz, CDCl₃) δ 8.15-8.13 (m, 1H), 7.48-7.42 (m, 1H),6.60-6.50 (m, 2H), 6.10 (s, 1H), 4.61 (s, 2H), 4.24-4.21 (m, 1H),4.07-4.01 (m, 1H), 3.62-3.55 (m, 2H), 3.10-3.03 (m, 1H), 2.37 (s, 3H),2.27-2.25 (m, 1H), 1.26- 1.21 (m, 4H), 1.05-0.95 (m, 2H). 5.8 

401.0  ¹H NMR (300 MHz, DMSO- d₆) δ 8.00-7.91 (m, 2H), 7.00- 6.94 (m,2H), 6.70-6.62 (m, 2H), 5.84 (s, 1H), 4.35 (s, 2H), 3.48-3.45 (m, 2H),2.20 (s, 3H), 1.14-1.10 (m, 3H). 5.9 

400.1  ¹H NMR (300 MHz, CD₃OD) δ 7.61-7.59 (m, 1H), 7.11-7.07 (m, 2H),6.92-6.85 (m, 2H), 6.67-6.62 (m, 2H), 6.00 (s, 1H), 4.36 (s, 2H),3.52-3.49 (m, 2H), 2.24 (s, 3H), 1.21- 1.18 (m, 3H). 5.10

402.9  ¹H NMR (300 MHz, CD₃OD) δ 9.06 (s, 1H), 8.71 (s, 2H), 7.23-7.18(m, 1H), 6.87-6.84 (m, 3H), 5.88 (s, 1H), 4.38 (s, 2H), 3.52-3.45 (m,2H), 2.19 (s, 3H), 1.19-1.12 (m, 3H). 5.11

409.8  ¹H NMR (300 MHz, DMSO- d₆) δ 7.94-7.90 (m, 1H), 7.25- 7.24 (m,1H), 7.00-6.94 (m, 2H), 6.63-6.52 (m, 3H), 5.90 (br, 2H), 5.74 (s, 1H),4.31 (s, 2H), 3.46-3.44 (m, 2H), 2.05 (s, 3H), 1.14-1.10 (m, 3H) 5.12

379.0  ¹H NMR (300 MHz, CD₃OD) δ 9.13 (s, 1H), 8.77 (s, 2H), 7.99-7.97(m, 1H), 7.51-7.45 (m, 1H), 6.66-6.55 (m, 2H), 5.91 (s, 1H), 4.61 (s,2H), 3.65-3.57 (m, 2H), 2.26 (s, 3H), 1.21-1.19 (m, 3H). 5.13

368.0  ¹H NMR (300 MHz, CDCl₃) δ 9.25 (s, 1H), 8.72 (s, 2H), 6.95-6.86(m, 2H), 6.69-6.65 (m, 2H), 6.23 (s, 1H), 4.25 (s, 2H), 2.32 (s, 3H).5.14

374.1  ¹H NMR (300 MHz, CD₃OD) δ 6.91-6.83 (m, 2H), 6.65-6.59 (m, 2H),6.00 (s, 1H), 4.30 (s, 2H), 3.51-3.44 (m, 2H), 3.14- 3.09 (m, 2H),1.61-1.51 (m, 2H), 1.42-1.30 (m, 2H), 1.17- 1.11 (m, 3H), 0.92-0.85 (m,3H) 5.15

422.1  ¹H NMR (300 MHz, CD₃OD) δ 9.17 (s, 1H), 8.89 (s, 2H), 6.93-6.87(m, 2H), 6.68-6.64 (m, 2H), 6.05 (s, 1H), 4.38 (s, 2H), 3.57-3.51 (m,2H), 1.99- 1.91 (m, 1H), 1.23-1.20 (m, 3H), 1.11-1.04 (m, 2H), 0.91-0.79 (m, 2H). 5.16

410.0  ¹H NMR (300 MHz, CD₃OD) δ 9.18 (s, 1H), 8.82 (s, 2H), 6.92-6.89(m, 2H), 6.68-6.64 (m, 2H), 6.04 (s, 1H), 4.39 (s, 2H), 3.37-3.34 (m,2H), 2.69- 2.67 (m, 2H), 1.29-1.14 (m, 6H). 5.17

402.1  ¹H NMR (300 MHz, CDCl₃) δ 6.94-6.77 (m, 2H), 6.58-6.34 (m, 2H),6.19 (s, 1H), 4.28 (s, 2H), 4.17-4.03 (m, 2H), 3.50- 3.43 (m, 2H),3.08-3.05 (m, 1H), 2.38 (s, 3H), 2.29-2.24 (m, 1H), 1.29-1.19 (m, 4H),1.06-0.94 (m, 2H) 5.18

402.1  ¹H NMR (300 MHz, CDCl₃) δ 6.94-6.77 (m, 2H), 6.58-6.34 (m, 2H),6.19 (s, 1H), 4.28 (s, 2H), 4.17-4.03 (m, 2H), 3.50- 3.43 (m, 2H),3.08-3.05 (m, 1H), 2.38 (s, 3H), 2.29-2.24 (m, 1H), 1.29-1.19 (m, 4H),1.06-0.94 (m, 2H) 5.19

402.1  ¹H NMR (300 MHz, CDCl₃) δ 6.94-6.77 (m, 2H), 6.58-6.34 (m, 2H),6.19 (s, 1H), 4.28 (s, 2H), 4.17-4.03 (m, 2H), 3.50- 3.43 (m, 2H),3.08-3.05 (m, 1H), 2.38 (s, 3H), 2.29-2.24 (m, 1H), 1.29-1.19 (m, 4H),1.06-0.94 (m, 2H) 5.20

401.2  5.21

395.1  ¹H NMR (400 MHz, DMSO- d₆) δ 8.57 (dd, J = 5.0, 1.5 Hz, 1H), 8.54(d, J = 2.0 Hz, 1H), 7.78 (dt, J = 8.1, 1.9 Hz, 1H), 7.42 (dd, J = 7.8,5.0 Hz, 1H), 6.97 (t, J = 8.9 Hz, 2H), 6.62 (dd, J = 9.2, 4.3 Hz, 2H),5.81 (s, 1H), 4.35 (s, 2H), 3.46 (q, J = 7.0 Hz, 2H), 2.16 (s, 3H), 1.13(t, J = 6.9 Hz, 3H). 5.22

394.1  ¹H NMR (400 MHz, DMSO- d₆) δ 7.39 (d, J = 5.5 Hz, 3H), 7.32 (d, J= 5.2 Hz, 2H), 6.98 (t, J = 8.6 Hz, 2H), 6.62 (dd, J = 9.1, 4.3 Hz, 2H),5.78 (s, 1H), 4.34 (s, 2H), 3.47 (q, J = 7.0 Hz, 2H), 2.13 (s, 3H), 1.13(t, J = 7.0 Hz, 3H). 5.23

332.1  ¹H NMR (400 MHz, DMSO- d₆) δ 6.98 (t, J = 8.6 Hz, 2H), 6.61 (dd,J = 9.0, 4.3 Hz, 2H), 5.81 (s, 1H), 4.30 (s, 2H), 3.47 (q, J = 7.0 Hz,2H), 2.59 (s, 3H), 2.28 (s, 3H), 1.13 (t, J = 7.0 Hz, 3H). 5.24

413.1  ¹H NMR (400 MHz, DMSO- d₆) δ 8.62 (d, J = 2.6 Hz, 1H), 8.45 (s,1H), 7.91-7.79 (m, 1H), 6.98 (t, J = 8.7 Hz, 2H), 6.62 (dd, J = 9.1, 4.3Hz, 2H), 5.83 (s, 1H), 4.36 (s, 2H), 3.47 (q, J = 7.0 Hz, 2H), 2.19 (s,3H), 1.13 (t, J = 6.9 Hz, 3H). 5.25

412   5.26

358.1  ¹H NMR (400 MHz, DMSO- d₆) δ 6.98 (t, J = 8.8 Hz, 2H), 6.61 (dd,J = 9.2, 4.3 Hz, 2H), 5.82 (s, 1H), 4.28 (s, 2H), 3.46 (q, J = 7.0 Hz,2H), 2.34 (s, 3H), 2.14 (p, J = 7.4 Hz, 1H), 1.13 (t, J = 7.0 Hz, 3H),0.97- 0.88 (m, 2H), 0.72-0.60 (m, 2H). 5.27

396.1  5.28

374.1  5.29

358.1  ¹H NMR (400 MHz, DMSO- d₆) δ 6.98 (t, J = 8.6 Hz, 2H), 6.61 (dd,J = 9.0, 4.3 Hz, 2H), 5.86 (s, 1H), 5.35 (s, 1H), 5.00 (s, 1H), 4.33 (s,2H), 3.47 (q, J = 7.0 Hz, 2H), 2.28 (s, 2H), 1.94 (s, 3H), 1.13 (t, J =7.0 Hz, 3H). 5.30

396.1  ¹H NMR (400 MHz, DMSO- d₆) δ 9.28 (d, J = 6.7 Hz, 1H), 9.22 (d, J= 1.5 Hz, 1H), 7.72 (d, J = 5.1 Hz, 1H), 7.03-6.91 (m, 2H), 6.69-6.55(m, 2H), 5.87 (s, 1H), 4.36 (s, 2H), 3.47 (q, J = 7.0 Hz, 2H), 2.22 (s,3H), 1.13 (t, J = 7.0 Hz, 3H). 5.31

429.1  ¹H NMR (400 MHz, DMSO- d₆) δ 8.65 (d, J = 3.0 Hz, 1H), 8.54 (s,1H), 8.03 (s, 1H), 6.98 (t, J = 8.7 Hz, 2H), 6.62 (dd, J = 9.2, 4.3 Hz,2H), 5.83 (s, 1H), 4.36 (s, 2H), 3.47 (q, J = 7.0 Hz, 2H), 2.19 (s, 3H),1.13 (t, J = 7.0 Hz, 3H). 5.32

395.1  5.33

398.2  5.34

384.1  5.35

420.1  ¹H NMR (400 MHz, DMSO- d₆) δ 9.04 (s, 1H), 8.87 (d, J = 1.7 Hz,1H), 8.41 (s, 1H), 6.98 (t, J = 8.7 Hz, 2H), 6.62 (dd, J = 9.3, 4.3 Hz,2H), 5.84 (s, 1H), 4.36 (s, 2H), 3.47 (q, J = 7.0 Hz, 2H), 2.21 (s, 3H),1.13 (t, J =7.0 Hz, 3H). 5.36

463.1  ¹H NMR (400 MHz, DMSO- d₆) δ 9.00 (s, 1H), 8.89 (s, 1H), 8.31 (s,1H), 6.98 (t, J = 8.7 Hz, 2H), 6.62 (dd, J = 9.0, 4.1 Hz, 2H), 5.83 (s,1H), 4.36 (s, 2H), 3.47 (q, J = 7.0 Hz, 2H), 2.20 (s, 3H), 1.13 (t, J =7.0 Hz, 3H). 5.37

385.1  ¹H NMR (300 MHz, CD₃OD) δ 8.09 (s, 1H), 7.38 (s, 1H), 6.94-6.88(m, 2H), 6.69-6.65 (m, 2H), 6.09 (s, 1H), 4.40 (s, 2H), 3.56-3.51 (m,2H), 2.36 (s, 3H), 1.24-1.19 (m, 3H)

Example 5.38:7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-3-(trifluoromethyl)-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-bromo-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(from Example 5.1, Step 1) (200 mg, 0.50 mmol) in N-methyl-pyrrolidone(5 mL) was added copper(I) iodide (12 mg, 0.06 mmol) and methyl2,2-difluoro-2-(fluorosulfonyl)acetate (146 mg, 0.76 mmol). The reactionsolution was stirred for 8 h at 120° C. The resulting mixture wasconcentrated in vacuo. The residue was purified by chromatography withethyl acetate/petroleum ether (1/2) to afford7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-3-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(21.1 mg, 11%) as a white solid. LCMS (ESI): M+H⁺=385.8; ¹H NMR (300MHz, CDCl₃) δ 6.94-6.88 (m, 2H), 6.59-6.54 (m, 2H), 6.24 (s, 1H), 4.28(s, 2H), 3.46-3.43 (m, 2H), 2.60-2.51 (m, 3H), 1.24-1.22 (m, 3H).

Example 5.39:7-((ethyl(4-fluorophenyl)amino)methyl)-3-(trans-2-(fluoromethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

Step 1:(2-(7-((ethyl(4-fluorocyclohexa-2,4-dienyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)cyclopropyl)methylmethanesulfonate

To a solution of7-((ethyl(4-fluorocyclohexa-2,4-dienyl)amino)methyl)-3-(2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(from Example 5.17) (50 mg, 0.13 mmol) in dichloromethane (5 mL) wasadded methanesulfonyl chloride (22 mg, 0.19 mmol) and triethylamine (26mg, 0.26 mmol). The reaction mixture was stirred 30 mins at roomtemperature. The reaction solution was concentrated in vacuo to afford(2-(7-((ethyl(4-fluorocyclohexa-2,4-dienyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)cyclopropyl)methylmethanesulfonate (60 mg, crude). The crude product was used in next stepwithout further purification.

Step 2:7-((ethyl(4-fluorophenyl)amino)methyl)-3-(trans-2-(fluoromethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of[2-(7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)cyclopropyl]methylmethanesulfonate (60 mg, 0.13 mmol) in propan-2-ol (0.5 mL) was addedcesium fluoride (45.6 mg, 0.30 mmol). The reaction mixture was stirredfor 90 min at 80° C. and then concentrated in vacuo. The residue waspurified by Prep-HPLC to afford7-[[ethyl(4-fluorophenyl)amino]methyl]-3-[trans-2-(fluoromethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas a yellow solid (3.1 mg, 6.0%). LCMS (ESI): M+H⁺=390.1; ¹H NMR (300MHz, CDCl₃) δ 6.95-6.89 (m, 2H), 6.72-6.65 (m, 2H), 6.12 (s, 1H),4.72-4.26 (m, 2H), 3.52-3.45 (m, 2H), 2.41 (s, 3H), 2.28-2.22 (m, 1H),1.71-1.58 (m, 1H), 1.26-1.15 (m, 4H), 1.08-1.01 (m, 1H).

Example 5.40:3-ethyl-7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-ethenyl-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(prepared via a method similar to Example 5.1) (75.0 mg, 0.22 mmol) inmethanol (15 mL) was added palladium on carbon (100 mg). The reactionmixture was stirred overnight at room temperature under a hydrogenatmosphere. After filtration, the filtrate was concentrated in vacuo.The residue was purified by chromatography with ethyl acetate/petroleumether (1/5) to afford3-ethyl-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas a yellow solid (50 mg, 60%). LCMS (ESI): M+H⁺=346.1; ¹H NMR (300 MHz,CDCl₃) δ 6.96-6.90 (m, 2H), 6.73-6.67 (m, 2H), 6.14 (s, 1H), 4.30 (s,2H), 3.54-3.47 (m, 2H), 3.19-3.14 (m, 2H), 2.32 (s, 3H), 1.38-1.24 (m,6H).

The following compound was prepared using methods analogous to Example5.40:

LCMS No. Structure/Name (M + H) ¹H NMR 5.41

360.1 ¹HNMR (300 MHz, CDCl₃) δ 6.92-6.86 (m, 2H), 6.67-6.63 (m, 2H),6.09 (s, 1H), 4.26 (s, 2H), 3.48-3.44 (m, 2H), 3.10-3.05 (m, 2H),1.71-1.43 (m, 2H), 1.22-1.17 (m, 3H), 0.95-0.90 (m, 3H)

The following compounds were prepared using methods analogous to thosedescribed above:

LCMS No. Structure/Name (M + H) ¹H NMR 5.42

406.0 ¹H NMR (300 MHz, CDCl₃) δ 6.95-6.90 (m, 2H), 6.66-6.64 (m, 2H),6.16 (s, 1H), 4.73-4.71 (m, 1H), 4.62-4.95 (m, 1H), 4.45 (s, 2H),4.05-4.02 (m, 1H), 4.01-3.72 (m, 2H) 3.14-3.08 (m, 1H), 2.39 (s, 3H),2.27-2.00 (m, 1H), 1.29-1.24 (m, 1H), 1.05-0.97 (m, 2H). 5.43

406.0 ¹H NMR (300 MHz, CDCl₃) δ 6.94-6.89 (m, 2H), 6.63-6.60 (m, 2H),6.15 (s, 1H), 4.73-4.70 (m, 1H), 4.61-4.59 (m, 1H), 4.43 (s, 2H),4.05-4.02 (m, 1H), 3.80-3.71 (m, 2H) 3.12-3.07 (m, 1H), 2.39 (s, 3H),2.27-2.23 (m, 1H), 1.28-1.25 (m, 1H). 1.05-0.96 (m, 2H). 5.44

384.0 ¹H NMR (300 MHz, CDCl₃) δ 7.49-7.47 (m, 2H), 6.90-6.85 (m, 2H),6.58-6.54 (m, 2H), 6.45-6.44 (m, 1H). 6.09 (s, 1H), 4.28 (s, 2H),3.50-3.41 (m, 2H), 2.27 (s, 3H), 1.22-1.18 (m, 3H). 5.45

384.0 ¹H NMR (300 MHz, CD₃OD) δ 7.63 (s, 1H), 6.93-6.87 (m, 2H),6.67-6.52 (m, 4H), 6.04 (s, 1H), 4.37 (s, 2H), 3.57-3.48 (m, 2H), 2.32(s, 3H), 1.23-1.20 (m, 3H). 5.46

396.0 ¹H NMR (300 MHz, CD₃OD) δ 7.65 (s, 1H), 6.81-6.63 (m, 1H),6.72-6.54 (m, 3H), 6.26 (s, 1H), 6.24-6.19 (m, 1H), 4.13 (m, 2H),3.84-3.76 (m, 1H), 3.23-3.15 (m, 1H), 2.71-2.63 (m, 1H), 2.33 (s, 3H),1.31 (m, 3H). 5.47

400.0 ¹H NMR (300 MHz, CD₃OD) δ 7.45-7.42 (m, 2H), 7.07-7.06 (m, 1H),6.93-6.87 (m, 2H), 6.67-6.63 (m, 2H), 6.00 (s, 1H), 4.36 (s, 2H), 3.51(m, 2H), 2.23 (s, 3H), 1.21 (m, 3H). 5.48

408.0 ¹HNMR (300 MHz, CD₃OD) δ 9.19 (s, 1H), 8.84 (s, 2H), 6.84- 6.81(m, 1H), 6.71-6.64 (m, 1H), 6.26 (s, 1H), 6.24-6.20 (m, 1H), 4.25-4.05(m, 2H), 3.84-3.76 (m, 1H), 3.22-3.17 (m, 1H), 2.68-2.62 (m, 1H), 2.31(s, 3H), 1.35-1.33 (m, 3H). 5.49

415.1 ¹H NMR (300 MHz, CD₃OD) δ 7.40 (s, 1H), 6.91-6.84 (m, 2H),6.65-6.59 (m, 2H), 6.00 (s, 1H), 4.35 (s, 2H), 3.49-3.46 (m, 2H), 2.45(s, 3H), 2.25 (s, 3H), 1.19- 1.15 (m, 3H) 5.50

411.2 ¹H NMR (300 MHz, DMSO-d₆) δ 7.39-7.34 (m, 2H), 6.70-6.95 (m, 2H),6.64-6.59 (m, 2H), 6.26 (m, 1H), 5.81 (s, 1H), 4.33 (s, 2H), 3.50-3.43(m, 2H), 2.21 (s, 3H), 1.13-1.10 (m, 3H) 5.51

409.9 ¹H NMR (300 MHz, DMSO-d₆) δ 7.77 (s, 1H), 7.36-7.26 (m, 1H),6.96-6.90 (m, 2H), 6.59-6.54 (m, 2H), 6.40-6.32 (m, 1H), 6.22 (br, 2H),5.74 (s, 1H), 4.28 (s, 2H), 3.45-3.38 (m, 2H), 2.12 (s, 3H), 1.10-1.02(m, 3H) 5.52

356.0 ¹H NMR (300 MHz, CDCl₃) δ 6.93-6.87 (m, 2H), 6.59-6.55 (m, 2H),6.16 (s, 1H), 4.28 (s, 2H), 3.50-3.43 (m, 2H), 2.45 (s, 3H), 2.23 (s,3H), 1.27-1.20 (m, 3H) 5.53

344.0 ¹H NMR (300 MHz, CDCl₃) δ 7.17-7.13 (m, 1H), 6.92-6.87 (m, 2H),6.59-6.55 (m, 2H), 6.15 (s, 1H), 5.64-5.60 (m, 1H), 5.35-5.29 (m, 1H),4.28 (s, 2H), 3.50-3.43 (m, 2H), 2.42 (s, 3H), 1.24-1.19 (m, 3H) 5.54

424.0 ¹H NMR (300 MHz, CDCl₃) δ 6.92-6.86 (m, 2H), 6.58-6.52 (m, 2H),6.14 (s, 1H), 4.25 (s, 2H), 3.46-3.40 (m, 2H), 2.18-2.10 (m, 1H),1.25-1.15 (m, 5H), 0.89-0.78 (m, 2H). 5.55

450.1 1H NMR (400 MHz, DMSO-d₆) δ 7.29 (tt, J = 9.4, 2.5 Hz, 1H), 7.16(h, J = 4 8 Hz, 2H), 6 98 (t, J = 8.9 Hz, 2H), 6.62 (dd, J = 9.1, 4.3Hz, 2H), 5.82 (s, 1H), 4.34 (s, 2H), 3.46 (q, J = 7.0 Hz, 2H), 2.16 (s,3H), 1.13 (t, J = 7.0 Hz, 3H). 5.56

398.34 5.57

410.1 5.58

425.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.31 (d, J = 2.9 Hz, 1H), 8.14 (s,1H), 7.43 (d, J = 2.3 Hz, 1H), 6.98 (t, J = 8.7 Hz, 2H), 6.62 (dd, J =9.3, 4.3 Hz, 2H), 5.81 (s, 1H), 4.35 (s, 2H), 3.81 (s, 3H), 3.47 (q, J =7.0 Hz, 2H), 2.16 (s, 3H), 1.13 (t, J = 7.0 Hz, 3H).

Method 6 Example 6.1:7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-3-morpholino-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-bromo-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(250 mg, 0.63 mmol) (from Example 5.1, Step 1) in dimethyl sulfoxide (3mL) was added potassium phosphate (268 mg, 1.26 mmol), L-proline (22.0mg, 0.19 mmol), morpholine (165 mg, 1.89 mmol) and cuprous iodide (18.0mg, 0.09 mmol). The reaction mixture was stirred overnight at 90° C. Theresulting mixture was quenched with water (50 mL), extracted with ethylacetate (30 mL×3), washed with brine, dried over anhydrous sodiumsulfate and concentrated in vacuo. The residue was purified bychromatography with ethyl acetate/petroleum ether (1/2) to afford7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-3-(morpholin-4-yl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas a white solid (29.5 mg, 12%). LCMS (ESI): M+H⁺=403.0; ¹H NMR (300MHz, CDCl₃) δ 6.93-6.87 (m, 2H), 6.61-6.57 (m, 2H), 6.15 (s, 1H),3.91-3.87 (m, 2H), 3.76-3.59 (m, 4H), 3.50-3.43 (m, 2H), 2.64-2.60 (m,2H), 2.40 (s, 3H), 1.25-1.20 (m, 3H).

The following examples were prepared in a manner similar to Example 6.1:

LCMS No. Structure/Name (M + H) ¹H NMR 6.2

361.0 ¹H NMR (300 MHz, CDCl₃) δ 6.93-6.87 (m, 2H), 6.60-6.55 (m, 2H),6.12 (s, 1H), 4.28 (s, 2H), 3.50-3.43 (m, 2H), 2.76 (s, 6H), 2.31 (s,3H), 1.26-1.20 (m, 3H) 6.3

387.1 ¹H NMR (300 MHz, CDCl₃) δ 6.93-6.87 (m, 2H), 6.59-6.54 (m, 2H),6.07 (s, 1H), 4.29 (s, 2H), 3.49-3.42 (m, 2H), 3.19-3.15 (m, 4H), 2.28(s, 3H), 1.20-1.16 (m, 4H), 1.26-1.19 (m, 3H)

Method 7 Example 7.1:7-(((3,4-difluorophenyl)(ethyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile

To a solution of3-bromo-7-[[(3,4-difluorophenyl)(ethyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(prepared via a method similar to Example 5.1, Step 1) (100 mg, 0.24mmol) in N,N-dimethylformamide (5 mL) was added cuprous cyanide (43.0mg, 0.48 mmol). The reaction solution was stirred for 1.5 h at 100° C.The reaction solution was quenched by water (50 mL), extracted withdichloromethane, washed with brine, dried over anhydrous magnesiumsulfate and concentration in vacuo. The residue was purified bychromatography with dichloromethane/methanol (20/1) to afford7-[[(3,4-difluorophenyl)(ethyl)amino]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carbonitrile(43.1 mg, 47%) as an off-white solid. LCMS (ESI): M+H⁺=361.0; ¹H NMR(400 MHz, CD₃OD) δ 7.08-7.01 (m, 1H), 6.59-6.53 (m, 1H), 6.430-6.40 (m,1H), 6.16 (s, 1H), 4.41 (s, 2H), 3.56-3.51 (m, 2H), 2.67 (s, 3H),1.31-1.21 (m, 3H).

The following examples were prepared in a manner similar to Example 7.1:

LCMS No. Structure/Name (M + H) ¹H NMR 7.2

343.1 ¹H NMR (300 MHz, CDCl₃) δ 7.19-7.17 (m, 1H), 6.46- 6.32 (m, 3H),6.25 (s, 1H), 4.34 (s, 2H), 3.53-3.50 (m, 2H), 2.66 (s, 3H), 1.27-1.24(m, 3H). 7.3

343.0 ¹H NMR (400 MHz, DMSO- d₆) δ 6.99 (t, J = 8.7 Hz, 2H), 6.62 (dd, J= 9.1, 4.2 Hz, 2H), 6.01 (s, 1H), 4.36 (s, 2H), 3.48 (q, J = 7.0 Hz,2H), 2.61 (s, 3H), 1.13 (t, J = 7.0 Hz, 3H). 7.4

329.1 ¹H NMR (400 MHz, DMSO- d₆) δ 8.70 (s, 1H), 7.05-6.87 (m, 2H),6.71-6.54 (m, 2H), 6.02 (s, 2H), 4.37 (s, 2H), 3.47 (q, J = 7.0 Hz, 2H),1.13 (t, J = 7.0 Hz, 3H).

The following compounds were prepared using methods analogous to thosedescribed above:

LCMS No. Structure/Name (M + H) ¹H NMR 7.5

355.0 ¹H NMR (300 MHz, CD₃OD) δ 6.84-6.81 (m, 1H), 6.70- 6.64 (m, 1H),6.38 (s, 1H), 6.21-6.20 (m, 1H), 4.23-4.04 (m, 2H), 3.80-3.75 (m, 1H),3.22-3.14 (m, 1H), 2.72-2.67 (m, 1H), 2.66 (s, 3H), 1.34- 1.32 (m, 3H).7.6

350.0 ¹H NMR (300 MHz, CD₃OD) δ 7.35-7.29 (m, 1H), 7.00- 6.97 (m, 3H),6.13 (s, 1H), 4.49 (s, 2H), 3.64-3.56 (m, 2H), 2.66 (s, 3H), 1.30-1.23(m, 3H). 7.7

326.1 ¹H NMR (300 MHz, CDCl₃) δ 8.12-8.11 (m, 1H),7.50- 7.45 (m, 1H),6.61-6.52 (m, 2H), 6.19 (s, 1H), 4.65 (s, 2H), 3.61-3.54 (m, 2H), 2.65(s, 3H), 1.26-1.21 (m, 3H). 7.8

336.8 ¹H NMR (300 MHz, CD₃OD) δ 7.05-7.03 (m, 1H), 6.98- 6.93 (m, 1H),6.65-6.60 (m, 1H), 6.38 (s, 1H), 6.28-6.26 (m, 1H), 4.26-4.09 (m, 2H),3.83-3.73 (m, 1H), 2.24-2.16 (m, 1H), 2.69-2.66 (m, 1H), 2.64 (s, 3H),1.34-1.21 (m, 3H). 7.9

361.1 ¹H NMR (300 MHz, CDCl₃) δ 6.19-6.05 (m, 4H), 4.31 (s, 2H),3.48-3.45 (m, 2H), 2.66 (s, 3H), 1.26-1.23 (m, 3H)

Method 8 Example 8.1:6-[(N-ethyl-4-fluoro-anilino)methyl]-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one

Step 1: 2-bromocyclopentan-1-one

To a solution of cyclohexanone (5.00 g, 50.9 mmol) in dimethyl sulfoxide(30 mL) was added N-bromosuccinimide (11.1 g, 62.4 mmol). The reactionmixture was stirred 20 min at room temperature and then quenched withwater (300 mL). The reaction mixture was extracted with dichloromethane(100 mL×2), washed with brine, dried over anhydrous sodium sulfate andconcentrated in vacuo to afford 2-bromocyclopentan-1-one as a lightyellow oil (5.6 g, 58%). The crude product was used in next step withoutfurther purification. No LCMS signal.

Step 2: 4H,5H,6H-cyclopenta[d][1,3]thiazol-2-amine

To a solution of 2-bromocyclopentan-1-one (5.50 g, 33.7 mmol) in ethanol(50 mL) was added thiourea (3.30 g, 43.4 mmol) and sodium bicarbonate(4.80 g, 57.1 mmol). The reaction mixture was stirred at refluxovernight. After cooling to room temperature, the reaction was quenchedwith water (200 mL), extracted with dichloromethane (100 mL×3), washedwith brine, dried over anhydrous sodium sulfate and concentrated invacuo to afford 4H,5H,6H-cyclopenta[d][1,3]thiazol-2-amine as a brownsolid (2.0 g, 42%). LCMS (ESI): M+H⁺=141.1.

Step 3:10-(chloromethyl)-7-thia-1,9-diazatricyclo[6.4.0.0′[2,6]]dodeca-2(6),8,10-trien-12-one

A mixture of 4H,5H,6H-cyclopenta[d][1,3]thiazol-2-amine (2.00 g, 14.3mmol) and ethyl 4-chloro-3-oxobutanoate (3.50 g, 21.3 mmol) inpolyphosphoric acid (15 mL) was stirred for 1 h at 110° C. The reactionmixture cooled to room temperature, diluted with water (30 mL) andstirred for 1 h at 80° C. After cooling to room temperature, thereaction was quenched by water (200 mL), and the pH value of thesolution was adjusted to pH 8-9 with potassium carbonate, extracted withdichloromethane (100 mL×3), washed with brine, dried over sodium sulfateand concentrated in vacuo. The residue was purified by chromatogtaphywith 20% ethyl acetate in petroleum ether to afford10-(chloromethyl)-7-thia-1,9-diazatricyclo[6.4.0.0′[2,6]]dodeca-2(6),8,10-trien-12-oneas a brown solid (150 mg, 4.0%). LCMS (ESI): M+H⁺=241.1.

Step 4:6-[(N-ethyl-4-fluoro-anilino)methyl]-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one

To a solution of10-(chloromethyl)-7-thia-1,9-diazatricyclo[6.4.0.0′[2,6]]dodeca-2(6),8,10-trien-12-one(150 mg, 0.62 mmol) in acetonitrile (20 mL) was addedN-ethyl-4-fluoroaniline (105 mg, 0.75 mmol), potassium carbonate (150mg, 0.62 mmol), and potassium iodide (52 mg, 0.31 mmol). The reactionmixture was stirred overnight at 60° C. After cooling to roomtemperature, the reaction was quenched with water (100 mL), extractedwith dichloromethane (50 mL×3), washed with brine, dried over sodiumsulfate and concentrated in vacuo. The residue was purified bychromatography with 33% ethyl acetate in petroleum ether to afford6-[(N-ethyl-4-fluoro-anilino)methyl]-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-oneas a brown solid (47.8 mg, 22%). LCMS (ESI): M+H⁺=343.7; ¹H NMR (300MHz, DMSO-d₆) δ 7.00-6.94 (m, 2H), 6.61-6.58 (m, 2H), 5.87 (s, 1H), 4.32(s, 2H), 3.50-3.43 (m, 2H), 3.19-3.13 (m, 2H), 2.85-2.72 (m, 2H),3.37-2.30 (m, 2H), 1.16-1.09 (m, 3H).

The following examples were prepared in a manner similar to Example 8.1:

LCMS No. Structure/Name (M + H) ¹H NMR 8.2

358.1 ¹H NMR (300 MHz, DMSO-d₆) δ 7.19-6.96 (m, 2H), 6.61-6.57 (m, 2H),5.80 (s, 1H), 4.29 (s, 2H), 3.46-3.42 (m, 2H), 3.14 (m, 2H), 2.72-2.70(m, 2H), 1.75 (m, 4H), 1.14-1.09 (m, 3H).

Example 8.3:6-[(N-ethyl-4-fluoro-anilino)methyl]-1-(hydroxymethyl)-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one

Step 1: ethyl 3-bromo-2-oxocyclopentanecarboxylate

To a solution of ethyl 3-bromo-2-oxocyclopentanecarboxylate (780 mg,5.00 mmol) in chloroform (15 mL) was added bromine (800 mg, 5.01 mmol)dropwise with stirring. The resulting solution was stirred for 2 h atroom temperature. The resulting mixture was concentrated in vacuo toafford ethyl 3-bromo-2-oxocyclopentanecarboxylate as light yellow oil(1.30 g). The crude product was used in the next step without furtherpurification. No LCMS signal.

Step 2: ethyl 2-amino-5,6-dihydro-4H-cyclopenta[d]thiazole-4-carboxylate

To a solution of ethyl 3-bromo-2-oxocyclopentanecarboxylate (1.30 g,5.53 mmol) in 1,4-dioxane (20 mL) was added thiourea (420 mg, 5.52mmol). The resulting solution was refluxed for 12 h. After cooled downto room temperature, the reaction mixture was concentrated in vacuo. Theresidue was purified by chromatography with dichloromethane/methanol(20/1) to affordethyl-2-amino-5,6-dihydro-4H-cyclopenta[d]thiazole-4-carboxylate aslight yellow solid (600 mg, 51%). LCMS (ESI): M+H⁺=213; ¹H NMR (300 MHz,DMSO-d₆) δ 6.90 (br, 2H), 4.12-4.08 (m, 2H), 3.68-3.63 (m, 1H),2.82-2.40 (m, 4H), 1.29-1.25 (m, 3H).

Step 3: Ethyl6-(chloromethyl)-8-oxo-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidine-1-carboxylate

To a solution ofethyl-2-amino-5,6-dihydro-4H-cyclopenta[d]thiazole-4-carboxylate (1.00g, 4.70 mmol) and 4-methylbenzenesulfonic acid (170 mg, 1.00 mmol) intoluene (30 mL) was added methyl 4-chloro-3-oxobutanoate (1.40 g, 9.40mmol). The reaction mixture was stirred for 12 h at 125° C. with aDean-Stark apparatus to separate water. After cooled down to roomtemperature, the reaction mixture was concentrated in vacuo. The residuewas purified by chromatography with ethyl acetate/petroleum ether (1:2)to afford ethyl6-(chloromethyl)-8-oxo-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidine-1-carboxylateas light yellow solid (150 mg, 10%). LCMS (ESI): M+H⁺=313.0; ¹H NMR (300MHz, CDCl₃) δ 6.30 (s, 1H), 4.46-4.40 (m, 1H), 4.33 (s, 2H), 4.22-4.18(m, 2H), 3.03-2.87 (m, 3H), 2.62-2.54 (m, 1H), 1.29-1.25 (m, 3H).

Step 4: ethyl2-((ethyl(4-fluorophenyl)amino)methyl)-4-oxo-4,6,7,8-tetrahydrocyclopenta[4,5]thiazolo[3,2-a]pyrimidine-6-carboxylate

To a solution of ethyl10-(chloromethyl)-12-oxo-7-thia-1,9-diazatricyclo[6.4.0.0{circumflexover ( )}[2,6]]dodeca-2(6),8,10-triene-3-carboxylate (50.0 mg, 0.16mmol), potassium iodide (14 mg, 0.08 mmol) and potassium carbonate (45mg, 0.33 mmol) in acetonitrile (5 mL) was added N-ethyl-4-fluoroaniline(33.0 mg, 0.24 mmol). The reaction mixture was stirred overnight at 80°C. After filtration and concentration in vacuo, the residue was purifiedby chromatography with ethyl acetate/petroleum ether (1/2) to affordethyl10-[[ethyl(4-fluorophenyl)amino]methyl]-12-oxo-7-thia-1,9-diazatricyclo[6.4.0.0{circumflexover ( )}[2,6]]dodeca-2(6),8,10-triene-3-carboxylate as a light yellowsemi-solid (17.2 mg, 26%). LCMS (ESI): M+H⁺=416.0; ¹H NMR (300 MHz,CDCl₃) δ 6.92-6.87 (m, 2H), 6.60-6.55 (m, 2H), 6.14 (s, 1H), 4.50-4.45(m, 1H), 4.30 (s, 2H), 4.22-4.17 (m, 2H), 3.48-3.41 (m, 2H), 3.02-2.85(m, 3H), 2.60-2.55 (m, 1H), 1.29-1.19 (m, 6H).

Step 5:10-[[Ethyl(4-fluorophenyl)amino]methyl]-12-oxo-7-thia-1,9-diazatricyclo[6.4.0.0{circumflexover ( )}[2,6]]dodeca-2(6),8,10-triene-3-carboxylic acid

To a solution of ethyl10-[[ethyl(4-fluorophenyl)amino]methyl]-12-oxo-7-thia-1,9-diazatricyclo[6.4.0.0{circumflexover ( )}[2,6]]dodeca-2(6),8,10-triene-3-carboxylate (40 mg, 0.10 mmol),tetrahydrofuran (2 mL) and water (2 mL) was added lithium hydroxide (12mg, 0.50 mmol). The resulting solution was stirred overnight at roomtemperature. The pH value of the solution was adjusted to pH 2 withhydrochloric acid (1 mol/L) and extracted with dichloromethane (2×20mL). The combined organic layers were washed with brine, dried overanhydrous sodium sulfate and concentrated in vacuo to afford10-[[ethyl(4-fluorophenyl)amino]methyl]-12-oxo-7-thia-1,9-diazatricyclo[6.4.0.0{circumflexover ( )}[2,6]]dodeca-2(6),8,10-triene-3-carboxylic acid (30 mg, 80%) asa light yellow solid. The crude product was used in the next stepwithout further purification.

Step 6:6-[(N-ethyl-4-fluoro-anilino)methyl]-1-(hydroxymethyl)-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one

To a solution of10-[[ethyl(4-fluorophenyl)amino]methyl]-12-oxo-7-thia-1,9-diazatricyclo[6.4.0.0{circumflexover ( )}[2,6]]dodeca-2(6),8,10-triene-3-carboxylic acid (110 mg, 0.28mmol) and triethylamine (60 mg, 0.57 mmol) in tetrahydrofuran (10 mL)was added chloro(propan-2-yloxy)methanone (70 mg, 0.57 mmol) and thereaction mixture was stirred 0.5 h at room temperature. Then sodiumborohydride (22 mg, 0.58 mmol) in water (0.5 mL) was added. Theresulting solution was stirred for an additional 1 h at roomtemperature. The reaction was quenched with saturated aqueous ammoniumchloride and extracted with dichloromethane (3×20 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate and concentrated in vacuo. The residue was purified bychromatography with ethyl acetate/petroleum ether (1/1) to afford6-[(N-ethyl-4-fluoro-anilino)methyl]-1-(hydroxymethyl)-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one(51.2 mg, 48%) as a white solid. LCMS (ESI): M+H⁺=374.0; ¹H NMR (400MHz, CDCl₃) δ 6.94-6.90 (m, 2H), 6.60-6.57 (m, 2H), 6.27 (s, 1H), 4.35(s, 2H), 3.98-3.91 (m, 2H), 3.75-3.70 (m, 2H), 3.49-3.47 (m, 2H),3.01-2.95 (m, 1H), 2.88-2.82 (m, 1H), 2.74-2.68 (m, 1H), 2.27-2.22 (m,1H), 1.26-1.23 (m, 3H).

Examples 8.4 and 8.5:6-[(N-ethyl-4-fluoro-anilino)methyl]-1-(hydroxymethyl)-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one(Enantiomers 1 and 2)

The product of Example 8.3 was further purified by chiral SFC on aChiralpak AD (2×15 cm) column eluting with 25% methanol (0.1% NH₄OH)/CO₂at 100 bar at a flow rate of 70 mL/min. The peaks isolated were analyzedon Chiralpak AD (50×0.46 cm) column eluting with 25% methanol (0.1%NH₄OH)/CO₂, at 120 bar (flow rate 5 mL/min, 220 nm). From thisseparation two isomers were isolated.

Example 8.4 (Peak 2; Enantiomer 2)

Retention time=1.45 min; LCMS (ESI): M+H⁺=374.0; ¹H NMR (400 MHz, CDCl₃)δ 6.94-6.90 (m, 2H), 6.60-6.57 (m, 2H), 6.27 (s, 1H), 4.35 (s, 2H),3.98-3.91 (m, 2H), 3.75-3.70 (m, 2H), 3.49-3.47 (m, 2H), 3.01-2.95 (m,1H), 2.88-2.82 (m, 1H), 2.74-2.68 (m, 1H), 2.27-2.22 (m, 1H), 1.26-1.23(m, 3H).

Example 8.5 (Peak 1, Enantiomer 1)

Retention time=0.59 min; LCMS (ESI): M+H⁺=374.0 ¹H NMR (400 MHz, CDCl₃)δ 6.94-6.90 (m, 2H), 6.60-6.57 (m, 2H), 6.27 (s, 1H), 4.35 (s, 2H),3.98-3.91 (m, 2H), 3.75-3.70 (m, 2H), 3.49-3.47 (m, 2H), 3.01-2.95 (m,1H), 2.88-2.82 (m, 1H), 2.74-2.68 (m, 1H), 2.27-2.22 (m, 1H), 1.26-1.23(m, 3H).

The following compounds were prepared using methods analogous to thosedescribed above:

LCMS No. Structure/Name (M + H) ¹H NMR 8.6 

  6-[(N-ethyl-4-fluoro- anilino)methyl]spiro[2,3-dihydrocyclopenta[3,4]thiazolo[1,4-a]pyrimidine-1,1′-cyclopentane]-8-one 398.0 ¹H NMR (300 MHz, CDCl₃) δ6.91-6.88 (m, 2H), 6.65-6.60 (m, 2H), 6.14 (s, 1H), 4.30 (s, 2H),3.50-3.43 (m, 2H), 2.84-2.80 (m, 2H), 2.43-2.34 (m, 4H), 1.98- 1.86 (m,2H), 1.74-1.48 (m, 4H), 1.19-1.23 (m, 3H). 8.7 

  6-[(N-ethyl-4-fluoro-anilino)methyl]-2,3-dihydrocyclopenta[3,4]thiazolo[1,4- a]pyrimidine-1,8-dione 358.2 ¹H NMR(300 MHz, CDCl₃) δ 7.01-6.74 (m, 4H), 6.17 (s, 1H), 5.54 (s, 2H),3.47-3.43 (m, 2H), 3.22-3.19 (m, 2H), 3.09-3.07 (m, 2H), 1.20-1.13 (m,3H) 8.8 

  6-[(N-ethyl-4-fluoro-anilino)methyl]-1,1- dimethyl-2,3-dihydrocyclopenta[3,4]thiazolo[1,4- a]pyrimidin-8-one 372.0 ¹H NMR (300MHz, CD₃OD) δ 6.94-6.88 (m, 2H), 6.68-6.63 (m, 2H), 6.09 (s, 1H), 4.36(s, 2H), 3.56-3.49 (m, 2H), 2.92-2.89 (m, 2H), 2.39-2.37 (m, 2H), 1.49(s, 6H), 1.22-1.20 (m, 3H). 8.9 

  2-[(N-ethyl-4-fluoro-anilino)methyl]-8,9-dihydro-6H-pyrano[3,4]thiazolo[1,4- a]pyrimidin-4-one 360.0 ¹HNMR (300MHz, CDCl₃) δ 6.94-6.92 (m, 2H), 6.72 (m, 2H), 6.14 (s, 1H), 4.33-4.27(m, 2H), 3.50-3.46 (m, 2 H), 3.35-3.32 (m, 2H), 2.13-2.19 (m, 2H),1.28-1.26 (m, 3H). 8.10

  2-[(N-ethyl-4-fluoro-anilino)methyl]-7- methyl-8,9-dihydro-6H-pyrido[3,4]thiazolo[1,4-a]pyrimidin-4-one 373.0 ¹H NMR (300 MHz, CDCl₃)δ 6.94-6.86 (m, 2H), 6.59-6.52 (m, 2H), 6.12 (s, 1H), 4.28 (s, 2H), 4.22(s, 2H), 3.47-3.45 (m, 2H), 2.86 (s, 4H), 2.58 (s, 3H), 1.23- 1.21 (m,3H). 8.11

  6-[(N-ethyl-4-fluoro-anilino)methyl]-8-oxo- 2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidine-1- carboxamide 387.0 ¹H NMR(400 MHz, CDCl₃) δ 7.34 (s, 1H), 6.97-6.93 (m, 2H), 6.72-6.67 (m, 2H),6.29 (s, 1H), 5.26 (s, 1H), 4.51-4.49 (m, 1H), 4.37 (s, 2H), 3.52-3.49(m, 2H), 3.26-3.19 (m, 1H), 3.07-3.02 (m, 1H), 2.90-2.83 (m, 1H), 2.68-2.59 (m, 1H), 1.25-1.22 (m, 3H) 8.12

  6-[(N-ethyl- 4-fluoro-anilino)methyl]-8-oxo-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4- a]pyrimidine-1-carbonitrile 369.0 ¹H NMR(300 MHz, CDCl₃) δ 6.94-6.87 (m, 2H), 6.60-6.56 (m, 2H), 6.24 (s, 1H),4.71-4.68 (m, 1H), 4.31 (s, 2H), 3.49-3.46 (m, 2H), 3.21-2.87 (m, 4H),1.24- 1.21 (m, 3H). 8.13

  2-[6-[(N-ethyl-4-fluoro-anilino)methyl]-8- oxo-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-1- yl]acetonitrile 383.3 ¹H NMR(300 MHz, CD₃OD) δ 6.93-6.90 (m, 2H), 6.70-6.65 (m, 2H), 6.14 (s, 1H),4.40 (s, 2H), 4.02-3.90 (m, 1H), 3.57-3.50 (m, 2H), 3.17-2.85 (m, 5H),2.48- 2.41 (m, 1H), 1.25-1.22 (m, 3H). 8.14

  6-[(N-ethyl-4-fluoro-anilino)methyl]-1-(2-hydroxyethyl)-2,3-dihydro-1H- cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one 388.2 ¹H NMR (300 MHz, CDCl₃) δ 6.96-6.92 (m, 2H), 6.82-6.72 (m,2H), 6.24 (s, 1H), 4.34 (s, 2H), 3.92-3.90 (m, 1H), 3.66-3.55 (m, 2H),3.52-3.47 (m, 2H), 2.98- 2.90 (m, 1H), 2.84-2.66 (m, 2H), 2.28-2.22 (m,1H), 1.99-1.89 (m, 2H), 1.28-1.22 (m, 3H). 8.15

  2-((ethyl(4-fluorophenyl)amino)methyl)-6- (methoxymethyl)-7,8-dihydrocyclopenta[4,5]thiazolo[3,2- a]pyrimidin-4(6H)-one 388.0 ¹H NMR(300 MHz, CDCl₃) δ 6.94-6.90 (m, 2H), 6.61-6.58 (m, 2H), 6.18 (s, 1H),4.33 (s, 2H), 3.91-3.88 (m, 1H), 3.70-3.64 (m, 2H), 3.51-3.48 (m, 2H),3.32 (s, 3H), 2.99-2.48 (m, 4H), 1.26- 1.23 (m, 3H). 8.16

  2-[6-[(N-ethyl-4-fluoro-anilino)methyl]-8- oxo-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-1- yl]acetamide 401.2 ¹H NMR(300 MHz, CD₃OD) δ 6.23-6.19 (m, 2H), 6.69-6.65 (m, 2H), 6.12 (s, 1H),4.38 (s, 2H), 4.08-3.97 (m, 1H), 3.57-3.50 (m, 2H), 2.96-2.73 (m, 4H),2.48- 2.36 (m, 2H). 1.25-1.21 (m, 3H).

Method 9 Example 9.1:3-cyclohexyl-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

Step 1: 4-(cyclohex-1-en-1-yl)-5-methyl-1,3-thiazol-2-amine

To a solution of 4-bromo-5-methyl-1,3-thiazol-2-amine (from Example 4.1,Step 5) (130 mg, 0.67 mmol) in 1,4-dioxane (2 mL) was added2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (140 mg,0.67 mmol), potassium phosphate (171 mg, 0.81 mmol) andtetrakis(triphenylphosphine)palladium (78 mg, 0.070 mmol). The reactionmixture was stirred for 2 h at 90° C. and concentrated in vacuo. Theresidue was purified by silica gel chromatography with 3.3% methanol indichloromethane to afford4-(cyclohex-1-en-1-yl)-5-methyl-1,3-thiazol-2-amine as a yellow solid(140 mg). The crude product was used in next step without furtherpurification. LCMS (ESI): M+H⁺=194.8.

Step 2: 4-cyclohexyl-5-methyl-1,3-thiazol-2-amine

To a solution of 4-(cyclohex-1-en-1-yl)-5-methyl-1,3-thiazol-2-amine(140 mg, 0.72 mmol) in MeOH (20 mL) was added Pd/C (100 mg) and hydrogenchloride (0.1 mL, 12 mol/L). The reaction mixture was stirred overnightat 40° C. under a hydrogen atmosphere (5 atm), then filtered andconcentrated in vacuo to afford4-cyclohexyl-5-methyl-1,3-thiazol-2-amine as a yellow solid (130 mg).The crude product was used in next step without further purification.LCMS (ESI): M+H⁺=197.1.

Step 3:7-(chloromethyl)-3-cyclohexyl-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a solution of 4-cyclohexyl-5-methyl-1,3-thiazol-2-amine (130 mg, 0.66mmol) in polyphosphoric acid (10 mL) was added ethyl4-chloro-3-oxobutanoate (164 mg, 1.00 mmol). The reaction mixture wasstirred for 1 h at 100° C. and then quenched by water (100 mL). The pHvalue was adjusted to pH 8-9 with a sodium hydroxide solution (1 M). Theresulting solution was extracted with dichloromethane (50 mL×3), washedwith brine, dried over anhydrous sodium sulfate, and concentrated invacuo. The residue was purified by chromatography with ethylacetate/petroleum ether (1/1) to afford7-(chloromethyl)-3-cyclohexyl-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas a white solid (49 mg, 25%). LCMS (ESI): M+H⁺=297.1.

Step 4:3-cyclohexyl-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a solution of7-(chloromethyl)-3-cyclohexyl-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(49 mg, 0.17 mmol) in acetonitrile (20 mL) was added potassium carbonate(46 mg, 0.33 mmol), potassium iodide (14 mg, 0.08 mmol) andN-ethyl-4-fluoroaniline (28 mg, 0.20 mmol). The reaction mixture wasstirred overnight at 60° C. and then quenched by water (100 mL). Thereaction mixture was extracted with dichloromethane (50 mL×3), washedwith brine, dried over anhydrous sodium sulfate, and concentrated invacuo. The residue was purified by chromatography with ethylacetate/petroleum ether (1/2) to afford3-cyclohexyl-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas a gray solid (8.8 mg, 13%). LCMS (ESI): M+H⁺=399.9; ¹H NMR (300 MHz,CDCl₃) δ 6.94-6.85 (m, 2H), 6.58-6.54 (m, 2H), 6.07 (s, 1H), 4.25 (s,2H), 3.48-3.41 (m, 2H), 2.41 (s, 3H), 1.87-1.71 (m, 6H), 1.41-1.30 (m,4H), 1.25-1.20 (m, 3H).

The following example was prepared in a manner similar to Example 9.1:

LCMS No. Structure/Name (M + H) ¹H NMR 9.2

  7-[(N-ethyl-4-fluoro-anilino)methyl]-3-isopropyl-2-methyl-thiazolo[3,2- a]pyrimidin-5-one 360.0 ¹H NMR (300MHz, CD₃OD) δ 6.91-6.87 (m, 2H), 6.69-6.19 (m, 2H), 6.05 (s, 1H), 4.33(s, 2H), 3.55-3.51 (m, 2H), 2.44 (s, 3H), 2.10 (m, 1H), 1.41-1.38 (m,6H), 1.19-1.21 (m, 3H).

The following compounds were prepared using methods analogous to thosedescribed above:

LCMS No. Structure/Name (M + H) ¹H NMR 9.3

  3-cyclopentyl-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2- a]pyrimidin-5-one 386.0 ¹H NMR(300 MHz, CD₃OD) δ 6.93-6.87 (m, 2H), 6.67-6.63 (m, 2H), 6.04 (s, 1H),4.33 (s, 2H), 4.17-4.08 (m, 1H), 3.53-3.47 (m, 2H), 2.41 (s, 3H),1.96-1.88 (m, 6H), 1.69-1.65 (m, 2H), 1.22- 1.19 (m, 3H). 9.4

  7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-tetrahydropyran-4-yl-thiazolo[3,2- a]pyrimidin-5-one 401.8 ¹HNMR (300 MHz, CDCl₃) δ 6.92-6.85 (m, 2H). 6.62-6.58 (m, 2H), 6.10 (s,1H), 4.67 (br, 1H), 4.26 (s, 2H), 4.06-4.01 (m, 2H), 3.55-3.42 (m, 4H),2.46 (s, 3H), 2.18-2.07 (m, 2H), 1.84-1.80 (m, 2H), 1.30-1.19 (m, 3H).

Method 10 Example 10.1:3-cyclobutyl-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one

Step 1: 2-Bromo-1-cyclobutylpropan-1-one

To a solution of 1-cyclobutylpropan-1-one (2.50 g, 22.3 mmol) inmethanol (50 mL) was added bromine (3.87 g, 24.2 mmol) under nitrogenatmosphere. The reaction solution was stirred overnight at roomtemperature and was then concentrated in vacuo to afford2-bromo-1-cyclobutylpropan-1-one as yellow oil (3.5 g). The crudeproduct was used for the next step without further purification.

Step 2: 4-Cyclobutyl-5-methyl-1,3-thiazol-2-amine

To a solution of 2-bromo-1-cyclobutylpropan-1-one (3.50 g, 31.3 mmol) inethanol (30 mL) was added thiourea (1.5 g, 19.71 mmol). The reactionsolution was heated to reflux for 1 h and then concentrated in vacuo.The residue was dissolved in dichloromethane (50 mL) and the solids werefiltered off. The resulting solution was concentrated in vacuo to afford4-cyclobutyl-5-methyl-1,3-thiazol-2-amine as a yellow solid (600 mg,18%). LCMS (ESI): M+H⁺=169.0.

Step 3:6-(Chloromethyl)-3-cyclobutyl-2-methyl-3aH,4H-thieno[2,3-b]pyridine-4-one

To a solution of 4-cyclobutyl-5-methyl-1,3-thiazol-2-amine (335 mg, 1.99mmol) was added polyphosphoric acid (5 mL) and ethyl4-chloro-3-oxobutanoate (492 mg, 2.99 mmol). The reaction solution wasstirred for 1 h at 110° C. The pH value of the solution was adjusted topH 9-10 with an aqueous sodium hydroxide solution (2 M). The reactionmixture was extracted with dichloromethane (5×100 mL), washed withbrine, dried over sodium sulfate and concentrated in vacuo to afford6-(chloromethyl)-3-cyclobutyl-2-methyl-3aH,4H-thieno[2,3-b]pyridine-4-oneas a brown solid (300 mg). The crude product was used in next stepwithout further purification. LCMS (ESI): M+H⁺=269.0.

Step 4:3-Cyclobutyl-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a solution of7-(chloromethyl)-3-cyclobutyl-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(300 mg, 1.12 mmol) in acetonitrile (20 mL) was added potassium iodide(93 mg, 0.56 mmol), potassium carbonate (309 mg, 2.24 mmol), andN-ethyl-4-fluoroaniline (311 mg, 2.23 mmol). The resulting solution wasstirred for 5 h at 70° C. After concentrating in vacuo, the crudeproduct was purified by Prep-HPLC with the following conditions (Agilent1200: Column, X-Brigde C18; mobile phase, 0.05% NH₄HCO₃ in water andCH₃CN (CH₃CN 20% up to 60% in 15 min); Detector, UV254) to afford3-cyclobutyl-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas a yellow solid (36.1 mg, 8%). LCMS (ESI): M+H⁺=371.8; ¹H NMR (300MHz, CD₃OD) δ 6.93-6.86 (m, 2H), 6.69-6.62 (m, 2H), 6.01 (s, 1H),4.44-4.35 (m, 1H), 4.31 (s, 2H), 3.53-3.49 (m, 2H), 2.48 (s, 3H),2.45-2.35 (m, 2H), 1.89-1.80 (m, 1H), 2.06-1.94 (m, 1H), 1.22-1.19 (m,3H).

The following examples were prepared in a manner similar to Example10.1:

LCMS No. Structure/Name (M+ H) ¹H NMR 10.2

  3-tert-butyl-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2- a]pyrimidin-5-one 374.0 ¹H NMR(300 MHz, CD₃OD) 6.94-6.91 (m, 2H), 6.68-6.63 (m, 2 H), 6.04 (s, 1H),4.31 (s, 2H), 3.53-3.50 (m, 2H), 2.54 (s, 3H), 1.59 (s, 9H), 1.23-1.20(m, 3H). 10.3

  3-acetyl-7-((ethyl(4- fluorophenyl)amino)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 360.1 ¹H NMR (300 MHz, CD₃OD) δ 6.95-6.89(m, 2H), 6.70-6.65 (m, 2H), 6.16 (s, 1H), 4.40 (s, 2H), 3.54-3.52 (m,2H), 2.40 (m, 6H), 1.24-1.21 (m, 3H). 10.4

  7-[(N- ethyl-4-fluoro-anilino)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide 375.2 ¹H NMR (300 MHz,DMSO-d₆) δ 8.37-8.36 (m, 1H), 7.14-6.95 (m, 2H), 6.68-6.59 (m, 2H), 5.90(s, 1H), 4.42 (s, 2H), 3.48-3.35 (m, 2H), 2.73-2.71 (m, 3H), 2.30 (s,3H), 1.13-1.11 (m, 3H).

Example 10.5:7-[(N-ethyl-4-fluoro-anilino)methyl]-3-(1-hydroxy-1-methyl-ethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-acetyl-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(from Example 10.3) (70 mg, 0.19 mmol) in tetrahydrofuran (15 mL) wasadded methylmagnesium bromide in tetrahydrofuran (1 mol/L, 0.42 mL). Thereaction was stirred for 48 h at room temperature and was then quenchedby a saturated aqueous ammonium chloride solution (20 mL). The resultingmixture was extracted with dichloromethane (3×30 mL), washed with brine,dried over anhydrous sodium sulfate, and concentrated in vacuo. Theresidue was purified chromatography with dichloromethane/methanol (50/1)to afford7-[[ethyl(4-fluorophenyl)amino]methyl]-3-(2-hydroxypropan-2-yl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas a yellow solid (40 mg, 52%). LCMS (ESI): M+H⁺=376.1; ¹H NMR (300 MHz,CD₃OD) δ 6.95-6.89 (m, 2H), 6.70-6.65 (m, 2H), 6.24 (s, 1H), 4.39 (s,2H), 3.56-3.50 (m, 2H), 2.58 (s, 3H), 1.73 (s, 6H), 1.24-1.21 (m, 3H).

Example 10.6:7-[(N-ethyl-4-fluoro-anilino)methyl]-3-(1-hydroxyethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one

Step 1:7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbaldehyde

To a solution of3-bromo-7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(from Example 5.1, Step 1) (200 mg, 0.51 mmol) in tetrahydrofuran (10mL) was added n-butyl lithium (0.3 ml, 2.5 mol/L) at −78° C., then wasstirred 30 min at the same temperature. Ethyl formate (75.8 mg, 1.02mmol) was added to the reaction mixture at −78° C. and allowed to warmto room temperature for 1 hour. The resulting reaction was quenched bywater (20 mL), extracted with dichloromethane (30 mL×3), washed withbrine, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by chromatography with 20% ethylacetate in petroleum ether to afford7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbaldehyde.LCMS (ESI): M+H⁺=345.1.

Step 2:7-[(N-ethyl-4-fluoro-anilino)methyl]-3-(1-hydroxyethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one

To a solution of7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carbaldehyde(200 mg, 0.58 mmol) (from example 11.4) in tetrahydrofuran (15 mL) wasadded methylmagnesium bromide (1.3 mL, 0.5 mol/L). The resultingsolution was stirred for overnight at room temperature. The reaction wasthen quenched by ammonium chloride (sat., 20 mL), extracted withdichloromethane (3×30 mL), washed with brine, dried over sodium sulfateand concentrated in vacuo. The residue was purified by chromatographywith ethyl acetate/petroleum ether (1/2) to afford7-[[ethyl(4-fluorophenyl)amino]methyl]-3-(1-hydroxyethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas an off-white solid (67.5 mg, 31%). LCMS (ESI): M+H⁺=362.1; ¹H NMR(300 MHz, CD₃OD) δ 6.95-6.88 (m, 2H), 6.71-6.65 (m, 2H), 6.20 (s, 1H),5.43-5.36 (m, 1H), 4.39 (s, 2H), 3.56-3.51 (m, 2H), 2.50 (s, 3H),1.54-1.51 (m, 3H), 1.24-1.21 (m, 3H).

Example 10.7:3-[(dimethylamino)methyl]-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a solution of7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carbaldehyde(from Example 10.6, Step 1) (100 mg, 0.29 mmol) in methanol (30 mL) wasadded dimethylamine hydrochloride (118 mg, 1.45 mmol), triethylamine(161 mg, 1.59 mmol) and sodium cyanoborohydride (55 mg, 0.88 mmol). Thereaction mixture was stirred overnight at room temperature and thenquenched by water (50 mL). The reaction mixture was extracted withdichloromethane (30 mL×3), washed with brine, dried over anhydroussodium sulfate, and concentrated under vacuum. The residue was purifiedby chromatography with 25% ethyl acetate in petroleum ether to afford3-[(dimethylamino)methyl]-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas a light yellow solid (11.1 mg, 10%). LCMS [M+H]⁺=374.85; ¹H NMR (300MHz, CDCl₃) δ 6.92-6.84 (m, 2H), 6.58-6.54 (m, 2H), 6.14 (s, 1H), 4.28(s, 2H), 4.05 (bs, 2H), 3.48-3.41 (m, 2H), 2.44-2.39 (m, 9H), 1.26-1.19(m, 3H).

The following examples were prepared in a manner similar to Example10.7:

LCMS No. Structure/Name (M + H) ¹H NMR 10.8 

  3-(azetidin-1-ylmethyl)-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2- a]pyrimidin-5-one 387.1 ¹H NMR(300 MHz, CD₃OD) δ 6.93-6.89 (m, 2H), 6.69-6.63 (m, 2H), 6.08 (s, 1H),4.36 (s, 2H), 4.27 (s, 2H), 3.56-3.52 (m, 2H), 3.33-3.31 (m, 4H), 2.41(s, 3H), 2.13-2.06 (m, 2H), 1.23-1.21 (m, 3H) 10.9 

  7-[(N-ethyl-4-fluoro-anilino)methyl]-2- methyl-3-(pyrrolidin-1-ylmethyl)thiazolo[3,2-a]pyrimidin-5-one 401.1 ¹H NMR (300 MHz, DMSO-d₆)δ 7.01-6.95 (m, 2H), 6.65-6.59 (m, 2H), 5.84 (s, 1H), 4.31 (s, 2H), 4.13(s, 2H), 3.48-3.43 (m, 2H), 2.50-2.49 (m, 4H), 2.38 (s, 3H), 1.75-1.73(m, 4H), 1.15-1.10 (m, 3H) 10.10

  7-[(N-ethyl-4-fluoro-anilino)methyl]-3-[(3-hydroxyazetidin-1-yl)methyl]-2-methyl- thiazolo[3,2-a]pyrimidin-5-one402.9 ¹H NMR (300 MHz, DMSO-d₆) δ 7.01-6.95 (m, 2H), 6.63-6.59 (m, 2H),5.83 (s, 1H), 5.22-5.20 (m, 1H), 4.31 (s, 2H), 4.11-4.01 (m, 3H),3.50-3.37 (m, 4H), 2.83-2.78 (m, 2H), 2.38 (s, 3H), 1.15-1.10 (m, 3H).

Example 10.11:7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-(2,2,2-trifluoro-1-hydroxyethyl)thiazolo[3,2-a]pyrimidin-5-one

To a solution of tetrabutylammonium fluoride (113 mg, 0.43 mmol) intetrahydrofuran (10 mL) was added 4 Å-molecular sieves (200 mg) and thenwas stirred for 0.5 h at −20° C. A solution of7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carbaldehyde(from Example 10.6, Step 1) (300 mg, 0.87 mmol),trimethyl(trifluoromethyl)silane (617 mg, 4.35 mmol) and 4 Å molecularsieve (100 mg) in tetrahydrofuran (20 mL) was added. The reactionmixture was stirred for an additional 3 h at −30° C. The reaction wasquenched with water (50 mL), extracted with dichloromethane (3×50 mL),washed with brine, dried over anhydrous magnesium sulfate andconcentrated in vacuo. The residue was purified by silica gelchromatography with dichloromethane/methanol (50/1) to afford7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-3-(2,2,2-trifluoro-1-hydroxyethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas a off-white solid (32.4 mg, 9.0%). LCMS (ESI): M+H⁺=416.0; ¹H NMR(300 MHz, CD₃OD) δ 6.95-6.89 (m, 2H), 6.69-6.64 (m, 2H), 6.12 (s, 1H),4.87 (s, 1H), 4.37 (s, 2H), 3.55-3.50 (m, 2H), 2.63 (s, 3H), 1.24-1.20(m, 3H).

Example 10.12:7-((ethyl(4-fluorophenyl)amino)methyl)-3-(hydroxymethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carbaldehyde(from Example 10.6, Step 1) (100 mg, 0.29 mmol) in tetrahydrofuran (10mL) was added water (2 mL) and sodium borohydride (33 mg, 0.87 mmol).The reaction mixture was stirred overnight at room temperature and thenquenched with water (50 mL). The resulting solution was extracted withethyl acetate (30 mL×3), washed with brine, dried over anhydrous sodiumsulfate, and concentrated in vacuo. The residue was purified bychromatography with 50% ethyl acetate in petroleum ether to afford7-[[ethyl(4-fluorophenyl)amino]methyl]-3-(hydroxymethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas a off-white solid (60 mg, 60%). LCMS (ESI): M+H⁺=347.9; ¹H NMR (300MHz, CDCl₃) δ 6.93-6.86 (m, 2H), 6.59-6.54 (m, 2H), 6.26 (s, 1H),4.75-4.73 (m, 2H), 4.49-4.45 (m, 1H), 4.32 (s, 2H), 3.52-3.44 (m, 2H),2.44 (s, 3H), 1.25-1.19 (m, 3H).

Example 10.13:7-[[ethyl(4-fluorophenyl)amino]methyl]-3-(methoxymethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a solution of7-[[ethyl(4-fluorophenyl)amino]methyl]-3-(hydroxymethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(60 mg, 0.17 mmol) in tetrahydrofuran (10 mL) was added sodium hydride(11 mg, 0.28 mmol) and iodomethane (30 mg, 0.21 mmol). The reactionmixture was stirred overnight at room temperature and then quenched bywater (100 mL). The resulting solution was extracted withdichloromethane (50 mL×3), washed with brine, dried over anhydroussodium sulfate, and concentrated in vacuo. The residue was purified bychromatography with 50% ethyl acetate in petroleum ether to afford7-[[ethyl(4-fluorophenyl)amino]methyl]-3-(methoxymethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas a yellow semi-solid (1.4 mg, 2.0%). LCMS (ESI): M+H⁺=362.1; ¹H NMR(300 MHz, CDCl₃) δ 6.93-6.87 (m, 2H), 6.61-6.60 (m, 2H), 6.16 (s, 1H),4.93 (s, 2H), 4.28 (s, 2H), 3.45-3.42 (m, 5H), 2.45 (s, 3H), 1.33-1.21(m, 3H).

Example 10.14:7-[[Ethyl(4-fluorophenyl)amino]methyl]-2-methyl-3-(1H-pyrazol-1-ylmethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a solution of7-[[ethyl(4-fluorophenyl)amino]methyl]-3-(hydroxymethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(from Example 10.12) (100 mg, 0.29 mmol), 1H-pyrazole (39.2 mg, 0.58mmol) and triphenylphosphine (135 mg, 0.52 mmol) in tetrahydrofuran (5mL) was added diisopropyl azodicarboxylate (105 mg, 0.52 mmol). Thereaction mixture was stirred at room temperature overnight. Afterconcentrating in vacuo, the crude residue was purified by silica gelchromatography with dichloromethane/methanol (100/1) to afford7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-3-(1H-pyrazol-1-ylmethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas an off-white solid (10.0 mg, 8.0%). LCMS (ESI): M+H⁺=398.1; ¹H NMR(300 MHz, CD₃OD) δ 7.76 (s, 1H), 7.45 (s, 1H), 6.93-6.87 (m, 2H),6.68-6.62 (m, 2H), 6.25 (s, 1H), 6.05 (s, 1H), 5.90 (s, 2H), 4.34 (s,2H), 3.53-3.47 (m, 2H), 2.58 (s, 3H), 1.22-1.19 (m, 3H).

Example 10.15:7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-(methylsulfonylmethyl)thiazolo[3,2-a]pyrimidin-5-one

Step 1:(7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)methylmethanesulfonate

To a solution of7-[[ethyl(4-fluorophenyl)amino]methyl]-3-(hydroxymethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(from Example 10.12) (100 mg, 0.28 mmol) in dichloromethane (15 mL) wasadded triethylamine (58 mg, 0.58 mmol) and methanesulfonyl chloride (50mg, 0.44 mmol) at 0° C. The reaction mixture was stirred for 30 min at0° C. and then concentrated under vacuum. The crude product was useddirectly in the next step.

Step 2:7-[[ethyl(4-fluorophenyl)amino]methyl]-3-(methanesulfonylmethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a solution of(7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)methylmethanesulfonate (120 mg, 0.28 mmol) in ethanol (30 mL) was added sodiummethanesulfinate (202 mg, 1.98 mmol). The reaction mixture was stirredat reflux for 2 h at 80° C. and then concentrated in vacuo. The residuewas purified by silica gel chromatography with dichloromethane/methanol(30/1) to afford7-[[ethyl(4-fluorophenyl)amino]methyl]-3-(methanesulfonylmethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas an off-white solid (2.8 mg, 2%). LCMS (ESI): M+H⁺=409.9; ¹H NMR (300MHz, DMSO-d₆) δ 6.94-6.88 (m, 2H), 6.57-6.52 (m, 2H), 5.84 (s, 1H), 5.28(s, 2H), 4.27 (s, 2H), 3.41-3.36 (m, 2H), 2.93 (s, 3H), 2.39 (s, 3H),1.08-1.03 (m, 3H) and3-(ethoxymethyl)-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas a off-white solid (22.1 mg, 21%). LCMS (ESI): M+H⁺=409.9; ¹H NMR (300MHz, DMSO-d₆) δ 6.94-6.88 (m, 2H), 6.57-6.52 (m, 2H), 5.84 (s, 1H), 5.28(s, 2H), 4.27 (s, 2H), 3.41-3.36 (m, 2H), 2.93 (s, 3H), 2.39 (s, 3H),1.08-1.03 (m, 3H).

The following examples were prepared in a manner similar to Example10.15:

LCMS No. Structure/Name (M + H) ¹H NMR 10.16

  3-(ethoxymethyl)-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2- a]pyrimidin-5-one 376.1 ¹H NMR(300 MHz, DMSO-d₆) δ 7.00-6.94 (m, 2H), 6.64-6.60 (m, 2H), 5.86 (s, 1H),4.87 (s, 2H), 4.32 (s, 2H), 3.49-3.47 (m, 4H), 2.41 (s, 3H), 1.15-1.05(m, 6H). 10.17

  2-[7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3- yl]acetonitrile 357.1 ¹H NMR(300 MHz, CDCl₃) δ 6.94-6.87 (m, 2H), 6.59-6.53 (m, 2H), 6.18 (s, 1H),4.41 (s, 2H), 4.28 (s, 2H), 3.48-3.41 (m, 2H), 2.41 (s, 3H), 1.25-1.19(m, 3H).

The following compounds were prepared using methods analogous to thosedescribed above:

LCMS No. Structure/Name (M + H) ¹H NMR 10.18

  3-tert-butyl-7-[(N-ethyl-4-fluoro-anilino)methyl]thiazolo[3,2-a]pyrimidin-5-one 360.0 ¹H NMR (300 MHz,CDCl₃) 6.92-6.89 (m, 2H), 6.64 (s, 1H), 6.61-6.56 (m, 2 H), 6.17 (s,1H), 4.29 (s, 2H), 3.48-3.45 (m, 2H), 1.55 (s, 9H), 1.24-1.21 (m, 3H).10.19

  7-[(N-ethyl-4-fluoro-anilino)methyl]-3-(1-hydroxy-1-methyl-ethyl)thiazolo[3,2- a]pyrimidin-5-one 362.1 ¹H NMR (400MHz, DMSO-d₆) δ 7.46-7.36 (m, 1H), 7.03-6.93 (m, 2H), 6.69-6.58 (m, 2H),6.48 (s, 1H), 6.11 (s, 1H), 4.40 (s, 2H), 3.49 (q, J = 7.0 Hz, 2H), 1.56(s, 6H), 1.14 (t, J = 7.0 Hz, 3H). 10.20

  7-[(N-ethyl-4-fluoro-anilino)methyl]-3-(1-hydroxyethyl)thiazolo[3,2-a]pyrimidin-5-one 348.1 ¹H NMR (400 MHz,DMSO-d₆) δ 7.03-6.92 (m, 2H), 6.67-6.59 (m, 2H), 5.92 (s, 1H), 5.48 (td,J = 6.6, 5.4 Hz, 1H), 7.31-7.25 (m, 1H), 4.34 (s, 2H), 3.47 (q, J = 7.0Hz, 2H), 1.37 (d, J = 6.3 Hz, 3H), 1.13 (t, J = 7.0 Hz, 3H). 10.21

  7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-(6-oxa-1-azaspiro[3.3]heptan-1-ylmethyl)thiazolo[3,2-a]pyrimidin-5-one 429.0 ¹H NMR (300 MHz, CD₃OD) δ6.96-6.88 (m, 2H), 6.70-6.64 (m, 2H), 6.08 (s, 1H), 5.14-5.10 (m, 2H),4.66-4.43 (m, 2H), 4.52 (s, 2H), 4.35 (s, 2H), 3.56- 3.51 (m, 2H),3.19-3.16 (m, 2H), 2.46 (s, 3H), 2.34-2.31 (m, 2H), 1.24-1.21 (m, 3H).10.22

  7-[(N-ethyl-4-fluoro-anilino)methyl]-3-[(2-hydroxyethylamino)methyl]-2-methyl- thiazolo[3,2-a]pyrimidin-5-one 391.1¹H NMR (300 MHz, CD₃OD) δ 6.89-6.83 (m, 2H), 6.64-6.59 (m, 2H), 6.08 (s,1H), 4.32 (s, 2H), 4.11 (s, 2H), 3.62-3.60 (m, 2H), 3.50-3.45 (m, 2H),2.69- 2.66 (m, 2H), 2.41 (s, 3H), 1.19-1.16 (m, 3H). 10.23

  3-(ethyl((3-(hydroxymethyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7- yl)methyl)amino)benzonitrile 354.9 ¹H NMR(300 MHz, DMSO-d₆) δ 7.34-7.28 (m, 1H), 7.01-6.92 (m, 3H), 5.92 (s, 1H),4.76 (s, 2H), 4.44 (s, 2H), 3.57-3.50 (m, 2H), 2.41 (s, 3H), 1.16-1.12(m, 3H). 10.24

  3-[ethyl-[[3-(methoxymethyl)-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-7- yl]methyl]amino]benzonitrile 369.0 ¹HNMR (300 MHz, DMSO-d₆) δ 7.34-7.28 (m, 1H), 7.02-6.93 (m, 3H), 5.85 (s,1H), 4.83 (s, 2H), 4.42 (s, 2H), 3.56-3.49 (m, 2H), 3.23 (s, 3H), 2.42(s, 3H), 1.16-1.11 (m, 3H). 10.25

  7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-3-((methylthio)methyl)-5H- thiazolo[3,2-a]pyrimidin-5-one 378.0¹H NMR (300 MHz, DMSO-d₆) δ 7.01-6.95 (m, 2H), 6.63-6.57 (m, 2H), 5.85(s, 1H), 4.32 (s, 2H), 4.22 (s, 2H), 3.50-3.43 (m, 2H), 2.37 (s, 3H),1.98 (s, 3H), 1.14-1.10 (m, 3H).

Method 11 Example 11.1:3-chloro-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-bromo-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(from Example 5.1, Step 1) (100 mg, 0.25 mmol) in tetrahydrofuran (20mL) was added n-butyl lithium (0.12 mL, 2.5 mol/L) dropwise at −80° C.The reaction solution was stirred for 30 min at −80° C. To the reactionwas added N-chlorosuccinimide (40 mg, 0.30 mmol) at −80° C. The reactionwas slowly warmed to room temperature for 30 min. The reaction was thenquenched by the addition of 100 mL of water, extracted with ethylacetate (30 mL×3), washed with brine, dried over anhydrous sodiumsulfate, and concentrated in vacuo. The residue was purified bychromatography with 33% ethyl acetate in petroleum ether to afford3-chloro-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas a yellow solid (16.4 mg, 18%). LCMS (ESI): M+H⁺=351.9; ¹H NMR (300MHz, CDCl₃) δ 6.94-6.88 (m, 2H), 6.61-6.57 (m, 2H), 6.16 (s, 1H), 4.27(s, 2H), 4.50-4.43 (m, 2H), 2.36 (s, 3H), 1.26-1.20 (m, 3H).

The following examples were prepared in a manner similar to Example11.1:

LCMS No. Structure/Name (M + H) ¹H NMR 11.2

  7-[(N-ethyl-4-fluoro-anilino)methyl]-3-fluoro-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 336.0 ¹H NMR (300 MHz, CDCl₃) δ7.63-7.00 (m, 2H), 6.88-6.70 (m, 2H), 6.46 (s, 1H), 4.20 (s, 2H),3.30-3.21 (m, 2H), 2.40 (s, 3H), 1.14-1.11 (m, 3H). 11.3

  7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 318.1 ¹H NMR (400 MHz, DMSO-d₆) δ7.84 (d, J = 1.8 Hz, 1H), 7.07- 6.90 (m, 2H), 6.66-6.50 (m, 2H), 5.93(s, 1H), 4.35 (s, 2H), 3.47 (q, J = 7.0 Hz, 2H), 2.42 (d, J = 1.4 Hz,3H), 1.13 (t, J = 7.0 Hz, 3H).

The following compounds were prepared using methods analogous to thosedescribed above:

LCMS No. Structure/Name (M + H) ¹H NMR 11.4

  7-[(N-ethyl-4-fluoro-anilino)methyl]-3-iodo-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 443.6 ¹H NMR (300 MHz, CDCl₃) δ6.95-6.90 (m, 2H), 6.71-6.68 (m, 2H), 6.19 (s, 1H), 4.29 (s, 2H),4.52-4.45 (m, 2H), 2.39 (s, 3H), 1.25-1.21 (m, 3H). 11.5

  3-chloro-7-[(N-ethyl-4-fluoro-anilino)methyl]thiazolo[3,2-a]pyrimidin-5-one 338.1 ¹H NMR (300 MHz,CDCl₃) δ 7.57 (s, 1H), 7.55-7.52 (m, 2H), 7.44-7.40 (m, 1H), 4.06-4.00(m, 3H), 3.22-3.17 (m, 1H), 2.37 (s, 3H), 2.31-2.26 (m, 1H), 1.34- 1.25(m, 1H), 1.06-0.98 (m, 2H). 11.6

  7-[(N-ethylanilino)methyl]-2-methyl- thiazolo[3,2-a]pyrimidin-5-one300.0 ¹H NMR (400 MHz, DMSO-d₆) δ 7.84 (s, 1H), 7.14 (t, J = 7.8 Hz,2H), 6.62 (t, J = 7.5 Hz, 2H), 5.92 (s, 1H), 4.38 (s, 2H), 3.50 (q, J =7.0 Hz, 2H), 2.42 (s, 3H), 1.15 (t, J = 7.0 Hz, 3H).

Method 12 Example 12.1:3-(1,3-dihydroxypropyl)-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one

Step 1:3-[3-(Benzyloxy)-1-hydroxypropyl]-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-bromo-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(from Example 5.1, Step 1) (600 mg, 1.51 mmol) in tetrahydrofuran (50mL) was added n-butyl lithium in tetrahydrofuran (2.4 M, 3 mL, 7.2 mmol)at −80° C. After stirring at −80° C. for 0.5 h, 3-(benzyloxy)propanal(500 mg, 3.05 mmol) was added to the reaction. The resulting solutionwas stirred for 1.5 h at −80° C. The reaction was then quenched by water(50 mL), extracted with dichloromethane (3×50 mL), washed with brine,dried over sodium sulfate and concentrated in vacuo to afford3-[3-(benzyloxy)-1-hydroxypropyl]-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas a yellow solid (500 mg). The crude product was used in next stepwithout purification. LCMS (ESI): M+H⁺=482.0.

Step 2:3-(1,3-Dihydroxypropyl)-7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-[3-(benzyloxy)-1-hydroxypropyl]-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(500 mg, 1.04 mmol) in dichloromethane (50 mL) was added a solution ofboron trichloride (10 mL, 1 mol/L) in dichloromethane (10 mL) at −20° C.The reaction mixture was stirred overnight at room temperature. Thereaction was quenched by a saturated aqueous ammonium chloride solution(50 mL), extracted with dichloromethane (3×50 mL), washed with brine,dried over sodium sulfate and concentrated in vacuo. The residue waspurified by chromatography with ethyl acetate/petroleum ether (1/1) toafford3-(1,3-dihydroxypropyl)-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas a off-white solid (136.4 mg, 32%). LCMS (ESI): M+H⁺=392.1; ¹H NMR(300 MHz, CD₃OD) δ 6.95-6.88 (m, 2H), 6.70-6.65 (m, 2H), 6.22 (s, 1H),5.32-5.27 (m, 1H), 4.40 (s, 2H), 3.75-3.67 (m, 1H), 3.57-3.49 (m, 3H),2.51 (s, 3H), 2.22-2.10 (m, 1H), 2.00-1.94 (m, 1H), 1.24-1.22 (m, 3H).

Example 12.2:7-[(N-ethyl-4-fluoro-anilino)methyl]-3-(1-fluoro-3-hydroxy-propyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one

Step 1:3-(3-(tert-butyldimethylsilyloxy)-1-fluoropropyl)-7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-[3-[(tert-butyldimethylsilyl)oxy]-1-hydroxypropyl]-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(prepared via a similar method as Example 12.1, Step 1) (120 mg, 0.24mmol) in dichloromethane (20 mL) was added diethylaminosulfurtrifluoride(57.4 mg, 0.36 mmol) dropwise at −78° C. The resulting solution wasstirred overnight at room temperature. The reaction was then quenched bya saturated aqueous sodium bicarbonate solution (20 mL), extracted withdichloromethane (3×20 mL), washed with brine, dried over sodium sulfateand concentrated in vacuo to afford3-[3-[(tert-butyldimethylsilyl)oxy]-1-fluoropropyl]-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas a yellow oil (100 mg). LCMS (ESI): M+H⁺=508.1.

Step 2:7-[[ethyl(4-fluorophenyl)amino]methyl]-3-(1-fluoro-3-hydroxypropyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-[3-[(tert-butyldimethylsilyl)oxy]-1-fluoropropyl]-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(50 mg, 0.10 mmol) in tetrahydrofuran (15 mL) was added hydrogenchloride (1 M, 2.5 mL) dropwise with stirring. The resulting solutionwas stirred for 3 h at room temperature. The reaction was then quenchedby a saturated aqueous sodium bicarbonate solution (20 mL), extractedwith dichloromethane (3×30 mL), washed with brine, dried over sodiumsulfate and concentrated in vacuo. The residue was purified bychromatography with dichloromethane/methanol (30/1) to afford7-[[ethyl(4-fluorophenyl)amino]methyl]-3-(1-fluoro-3-hydroxypropyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas a light yellow solid (12.2 mg, 30%). LCMS (ESI): M+H⁺=394.1; ¹H NMR(300 MHz, CD₃OD) δ 6.94-6.76 (m, 3H), 6.68-6.64 (m, 2H), 6.07 (s, 1H),4.35 (s, 2H), 3.79-3.71 (m, 2H), 3.55-3.48 (m, 2H), 2.52 (s, 3H),2.40-2.52 (m, 2H), 1.23-1.20 (m, 3H).

Examples 12.3 and 12.4:3-(1,3-dihydroxypropyl)-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one(Enantiomers 1 and 2)

The product of Example 12.1 was further purified by chiral SFC on aChiralpak AD (2×15 cm) column eluting with 25% methanol (0.1% NH₄OH)/CO₂at 100 bar at a flow rate of 70 mL/min. The peaks isolated were analyzedon Chiralpak AD (50×0.46 cm) column eluting with 25% methanol (0.1%NH₄OH)/CO₂, at 120 bar (flow rate 5 mL/min, 220 nm). From thisseparation two isomers were isolated.

Example 12.3 (Peak Enantiomer 1)

Retention time=1.54 min; LCMS (ESI): M+H⁺=392.1; ¹H NMR (300 MHz, CD₃OD)δ 6.95-6.88 (m, 2H), 6.70-6.65 (m, 2H), 6.22 (s, 1H), 5.32-5.27 (m, 1H),4.40 (s, 2H), 3.75-3.67 (m, 1H), 3.57-3.49 (m, 3H), 2.51 (s, 3H),2.22-2.10 (m, 1H), 2.00-1.94 (m, 1H), 1.24-1.22 (m, 3H).

Example 12.4 (Peak 2, Enantiomer 2)

Retention time=1.63 min; LCMS (ESI): M+H⁺=392.1; ¹H NMR (300 MHz, CD₃OD)δ 6.95-6.88 (m, 2H), 6.70-6.65 (m, 2H), 6.22 (s, 1H), 5.32-5.27 (m, 1H),4.40 (s, 2H), 3.75-3.67 (m, 1H), 3.57-3.49 (m, 3H), 2.51 (s, 3H),2.22-2.10 (m, 1H), 2.00-1.94 (m, 1H), 1.24-1.22 (m, 3H).

The following example was prepared in a manner similar to Example 12.1:

LCMS No. Structure/Name (M + H) ¹H NMR 12.5

  3-(1,2-dihydroxyethyl)-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2- a]pyrimidin-5-one 378.0 ¹H NMR(300 MHz, CDCl₃) 6.94-6.88 (m, 2H), 6.60-6.54 (m, 2H), 6.32 (s, 1H),6.02- 5.97 (m, 1H) 4.34 (s, 2H), 4.02-3.96 (m, 1H), 3.74-3.68 (m, 1H),3.48-3.46 (m, 2H), 2.47 (s, 3H), 1.25-1.20 (m, 3H)

Method 13 Example 13.1:7-[(N-ethyl-4-fluoro-anilino)methyl]-3-(3-hydroxypropyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one

Step 1:(E)-Ethyl-3-(7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)acrylate

To a solution of3-bromo-7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(from Example 5.1, Step 1) (400 mg, 1.01 mmol), tri(o-tolyl)phosphine(60 mg, 0.20 mmol), triethylamine (200 mg, 1.98 mmol) andtris(dibenzylideneacetone)dipalladium(0) (50 mg, 0.05 mmol) inacetonitrile (20 mL) was added ethyl acrylate (200 mg, 2.00 mmol). Thereaction mixture was stirred for 3 h at 90° C. and then concentrated invacuo. The residue was purified by chromatography with ethylacetate/petroleum ether (1/2) to afford(E)-ethyl-3-(7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)acrylateas a light yellow solid (280 mg, 67%). LCMS (ESI): M+H⁺=416.0; ¹H NMR(300 MHz, CDCl₃) δ 8.26-8.20 (m, 1H), 6.94-6.90 (m, 2H), 6.62-6.59 (m,2H), 6.20 (s, 1H), 6.02-5.98 (m, 1H), 4.31-4.27 (m, 4H), 3.50-3.47 (m,2H), 2.48 (s, 3H), 1.37-1.22 (m, 6H).

Step 2:Ethyl-3-(7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)propanoate

To a solution of(E)-ethyl-3-(7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)acrylatein methanol (10 mL) was added 10% palladium on carbon and the reactionsolution was stirred 12 h at room temperature under a hydrogenatmosphere (1.5 atm). After filtration the resulting solution wasconcentrated in vacuo to affordethyl-3-(7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)propanoateas a light yellow solid (180 mg, 90%). LCMS (ESI): M+H⁺=418.0; ¹H NMR(300 MHz, CDCl₃) δ 6.94-6.88 (m, 2H), 6.62-6.58 (m, 2H), 6.12 (s, 1H),4.28 (s, 2H), 4.13-4.10 (m, 2H), 3.51-3.41 (m, 4H), 2.74-2.71 (m, 2H),2.37 (s, 3H), 1.26-1.20 (m, 6H).

Step 3:7-((Ethyl(4-fluorophenyl)amino)methyl)-3-(3-hydroxypropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution ofethyl-3-(7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)propanoate(180 mg, 0.43 mmol) in methanol (10 mL) was added lithiumborohydride (20mg, 0.91 mmol) at 0° C. The resulting solution was stirred for 5 h atroom temperature. The reaction was then quenched by a saturated aqueousammonium chloride solution (20 mL), extracted with dichloromethane (3×50mL), washed with brine, dried over anhydrous sodium sulfate, and thenconcentrated in vacuo. The residue was purified by silica gelchromatography with dichloromethane/methanol (30/1) to afford7-((ethyl(4-fluorophenyl)amino)methyl)-3-(3-hydroxypropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-oneas a light yellow solid (100 mg, 62%). LCMS (ESI): M+H⁺=376.0; ¹H NMR(400 MHz, CDCl₃) δ 6.94-6.90 (m, 2H), 6.63-6.59 (m, 2H), 6.15 (s, 1H),4.31 (s, 2H), 3.68-3.66 (m, 2H), 3.50-3.47 (m, 2H), 3.35-3.32 (m, 2H),2.36 (s, 3H), 1.95-1.90 (m, 2H), 1.22-1.19 (m, 3H).

Example 13.2:7-((Ethyl(4-fluorophenyl)amino)methyl)-3-(3-methoxypropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of7-((ethyl(4-fluorophenyl)amino)methyl)-3-(3-hydroxypropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(50 mg, 0.13 mmol) in tetrahydrofuran (5 mL) was added sodium hydride(7.0 mg, 60%, 0.29 mmol) and stirred for 1 h at room temperature. Theniodomethane (100 mg, 0.70 mmol) was added to the reaction and theresulting solution was stirred 12 h at room temperature. The reactionwas quenched by water/ice (10 mL), extracted with dichloromethane (3×30mL), washed with brine, dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified by chromatography withethyl acetate/petroleum ether (1/3) to afford7-((ethyl(4-fluorophenyl)amino)methyl)-3-(3-methoxypropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-oneas a light yellow semi-solid (7.9 mg, 15%). LCMS (ESI): M+H⁺=390.1; ¹HNMR (300 MHz, CDCl₃) δ 6.91-6.82 (m, 2H), 6.56-6.52 (m, 2H), 6.07 (s,1H), 4.24 (s, 2H), 3.46-3.33 (m, 4H), 3.30 (s, 3H), 3.21-3.18 (m, 2H),2.29 (s, 3H), 1.93-1.85 (m, 2H), 1.22-1.19 (m, 3H).

The following example was prepared in a manner similar to Example 13.1and 13.2:

LCMS No. Structure/Name (M + H) ¹H NMR 13.3

  7-((Ethyl(4-fluorophenyl)amino)methyl)-3-(4-hydroxybutyl)-2-methyl-5H-thiazolo[3,2- a]pyrimidin-5-one 390.1 ¹H NMR(300 MHz, CDCl₃) δ 6.91-6.83 (m, 2H), 6.57-6.50 (m, 2H), 6.09 (s, 1H),4.25 (s, 2H), 3.71-3.68 (m, 2H), 3.45- 3.40 (m, 2H), 3.12-3.19 (m, 2H),2.35 (s, 1H), 2.29 (s, 3H), 1.74-1.60 (m, 4H), 1.23-1.18 (m, 3H).

Example 13.4:7-((Ethyl(4-fluorophenyl)amino)methyl)-3-(2-hydroxyethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

Step 1:3-[(E)-2-ethoxyvinyl]-7-[(N-ethyl-4-fluoroanilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-bromo-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(from Example 5.1, Step 1) (50 mg, 0.13 mmol) in 1,4-dioxane/water(0.6/0.2 mL) was added2-[(E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (40 mg,0.20 mmol), potassium phosphate (80 mg, 0.38 mmol) andtetrakis(triphenylphosphine)palladium (20 mg, 0.02 mmol). The resultingsolution was stirred for 3 h at 90° C. under nitrogen. After coolingdown to room temperature, the reaction mixture was concentrated invacuo. The residue was purified by chromatography with ethylacetate/petroleum ether (1/5) to afford the title compound as a lightyellow solid (16.9 mg, 35%). LCMS (ESI): M+H⁺=388.0; ¹H NMR: (300 MHz,CDCl₃): δ 6.93-6.85 (m, 2H), 6.60-6.51 (m, 2H), 6.52-5.48 (m, 1H),6.34-6.19 (m, 1H), 6.10 (s, 1H), 4.27 (s, 2H), 3.99-3.92 (m, 2H),3.53-3.42 (m, 2H), 2.38 (s, 3H), 1.38-1.35 (m, 3H), 2.23-2.19 (m, 3H).

Step 2:2-(7-((Ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)acetaldehyde

To a solution(E)-3-(2-ethoxyvinyl)-7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-onein acetone was added 3 N hydrogen chloride (15 mL). The resultingsolution was refluxed for 3 h in an oil bath. The pH value of thesolution was adjusted to pH 8 with a saturated aqueous sodiumbicarbonate solution. The mixture was extracted with dichloromethane(3×50 mL), washed with brine, dried over anhydrous sodium sulfate andconcentrated in vacuo to afford2-(7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)acetaldehydewas obtained as a light yellow oil (180 mg). The crude product was usedin the next step without further purification.

Step 3:7-((Ethyl(4-fluorophenyl)amino)methyl)-3-(2-hydroxyethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of2-(7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)acetaldehyde(180 mg, 0.50 mmol) in methanol (10 mL) was added sodium borohydride (40mg, 1.06 mmol) at 0° C. After stirring overnight at room temperature,the reaction was quenched by saturated aqueous ammonium chloride (20mL). The resulting solution was extracted with dichloromethane (3×50mL), washed with brine, dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified by chromatography withdichloromethane/methanol (30/1) to afford7-((ethyl(4-fluorophenyl)amino)methyl)-3-(2-hydroxyethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-oneas a white solid (90 mg, 50%). LCMS (ESI): M+H⁺=362.0; ¹H NMR (300 MHz,CDCl₃) δ 6.90-6.84 (m, 2H), 6.55-6.50 (m, 2H), 6.14 (s, 1H), 4.26 (s,2H), 3.89-3.87 (m, 2H), 3.47-3.39 (m, 4H), 2.32 (s, 3H), 1.21-1.18 (m,3H).

Example 13.5:7-[[Ethyl(4-fluorophenyl)amino]methyl]-3-(2-methoxyethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a solution of7-[[ethyl(4-fluorophenyl)amino]methyl]-3-(2-hydroxyethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(50 mg, 0.14 mmol) in tetrahydrofuran (5 mL) was added sodium hydride(11 mg, 0.46 mmol) at 0° C. After stirred 0.5 h at room temperature,iodomethane (11 mg, 0.08 mmol) was added to the reaction. After stirring3 h at room temperature, the reaction was quenched with water/ice (20mL), extracted with dichloromethane (3×30 mL), washed with brine, driedover anhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by chromatography with ethyl acetate/petroleum ether (1/3) toafford7-[[ethyl(4-fluorophenyl)amino]methyl]-3-(2-methoxyethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas a gray semi-solid (11.5 mg, 22%). LCMS (ESI): M+H⁺=376.0; ¹H NMR (300MHz, CDCl₃) δ 6.94-6.85 (m, 2H), 6.60-6.54 (m, 2H), 6.10 (s, 1H), 4.28(s, 2H), 3.69-3.66 (m, 2H), 3.49-3.39 (m, 4H), 3.31 (s, 3H), 2.33 (s,3H), 1.23-1.21 (m, 3H).

Example 13.6:3-(7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)propanamide

To a solution of ethyl3-(7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)propanoate(from Example 13.1, Step 2) (50 mg, 0.12 mmol) in a 10 mL sealed tubewas added 1 M ammonia in methanol (3 mL, 3 mmol). The reaction wassealed and stirred overnight at 80° C. and then concentrated in vacuo.The residue was purified by silica gel chromatography withdichloromethane/methanol (20/1) to afford3-(7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)propanamideas an off-white solid (10 mg, 21%). LCMS (ESI): M+H⁺=389.0; ¹H NMR (300MHz, CDCl₃) δ 6.97-6.92 (m, 2H), 6.74-6.72 (m, 2H), 6.19 (s, 1H), 4.32(s, 2H), 3.54-3.43 (m, 4H), 2.60-2.57 (m, 2H), 2.38 (s, 3H), 1.27-1.24(m, 3H).

Example 13.7:3-[7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]propanenitrile

To a solution of3-(7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)propanamide(50 mg, 0.13 mmol) and triethylamine (30 mg, 0.30 mmol) indichloromethane (10 mL) was added (trifluoromethane)sulfonyltrifluoromethanesulfonate (40 mg, 0.14 mmol) at 0° C. and then stirredat room temperature for 2 h. The reaction was quenched by saturatedaqueous sodium bicarbonate, extracted with dichloromethane (3×30 mL),washed with brine, dried over anhydrous sodium sulfate and concentratedin vacuo. The residue was purified by chromatography with ethylacetate/petroleum ether (1/1) to afford3-(7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)propanenitrileas an off-white solid (14 mg, 29%). LCMS (ESI): M+H⁺=370.9; ¹H NMR (300MHz, CDCl₃) δ 6.92-6.86 (m, 2H), 6.65-6.60 (m, 2H), 6.13 (s, 1H), 4.27(s, 2H), 3.49-3.41 (m, 4H), 2.87-2.86 (m, 2H), 2.42 (s, 3H), 1.22-1.19(m, 3H).

The following compound was prepared using methods analogous to thosedescribed above:

LCMS No. Structure/Name (M + H) ¹H NMR 13.8

  3-[7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]- N,N-dimethyl-propanamide417.2 ¹H NMR (400 MHz, CDCl₃) δ 6.94-6.89 (m, 2H), 6.60-6.57 (m, 2H),6.13 (s, 1H), 4.30 (s, 2H), 3.51-3.43 (m, 4H), 3.02 (s, 3H), 2.96 (s,3H), 2.71-2.69 (m, 2H), 2.37 (s, 3H), 1.24- 1.21 (m, 3H). 13.9

  7-[[Ethyl(4-fluorophenyl)amino]methyl]-3-(3-hydroxy-3-methylbutyl)-2-methyl-5H- [1,3]thiazolo[3,2-a]pyrimidin-5-one403.8 ¹H NMR (400 MHz, CD₃OD) δ 6.94-6.89 (m, 2H), 6.68-6.65 (m, 2H),6.06 (s, 1H), 4.35 (s, 2H), 3.56-3.51 (m, 2H), 3.27- 3.23 (m, 2H), 2.38(s, 3H), 1.77-1.73 (m, 2H), 1.26 (s, 6H), 1.24-1.21 (m, 3H).

Method 14 Example 14.1:2-[7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarboxamide

Step 1: ethyl2-(7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)cyclopropanecarboxylate

To a microwave tube with a solution of3-bromo-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(from Example 5.1, Step 1) (200 mg, 0.51 mmol) in acetonitrile/water(5/1 mL) was added ethyl2-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)cyclopropane-1-carboxylate(from Example 4.8, Step 1) (900 mg, 2.55 mmol), potassium carbonate (279mg, 2.04 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride (19 mg, 0.025 mmol). The resulting solution was stirred for 1h at 120° C. The resulting mixture was concentrated in vacuo. Theresidue was purified by chromatography with ethyl acetate/petroleumether (1/2) to afford ethyl2-(7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)cyclopropane-1-carboxylate(80 mg, 37%) as a yellow oil. LCMS (ESI): M+H⁺=430.1.

Step 2:2-(7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)cyclopropanecarboxylicacid

To a solution of ethyl2-(7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)cyclopropane-1-carboxylate(80 mg, 0.18 mmol) in tetrahydrofuran/water (20/3 mL) was added lithiumhydroxide (22 mg, 0.90 mmol). After stirring overnight at roomtemperature, the pH value of the solution was adjusted to off 4-5 with 1N HCl. The reaction mixture was extracted with ethyl acetate (200 mL),washed with brine, dried over anhydrous magnesium sulfate, concentratedin vacuo to afford2-(7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)cyclopropane-1-carboxylicacid as a yellow oil (80 mg). The crude product was used in next stepwithout further purification. LCMS (ESI): M+H⁺=402.1.

Step 3:2-[7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarboxamide

To a solution of2-(7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)cyclopropane-1-carboxylicacid (50 mg, 0.12 mmol) in tetrahydrofuran (10 mL) was addedtriethylamine (25 mg, 0.24 mmol), chloro(propan-2-yloxy)methanone (22.8mg, 0.19 mmol). The reaction solution was stirred for 10 min at roomtemperature. To the reaction was added 1 M ammonia in methanol (1 mL, 1mmol). The reaction solution was stirred for an additional 20 min atroom temperature. The resulting mixture was concentrated in vacuo. Theresidue was purified by chromatography with dichloromethane/methanol(20/1) to afford2-(7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)cyclopropane-1-carboxamideas a yellow solid (35 mg, 70%). LCMS (ESI): M+H⁺=400.9; ¹H NMR (400 MHz,CD₃OD) δ 6.86-6.83 (m, 2H),6.67-6.59 (m, 2H), 6.01 (s, 1H), 4.28 (s,2H), 3.54-3.41 (m, 2H), 2.63-2.61 (m, 1H), 2.38 (s, 3H), 1.87-1.81 (m,1H), 1.58-1.52 (m, 1H), 1.28-1.15 (m, 4H).

Example 14.2:2-[7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarboxamide

To a solution of2-(7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)cyclopropane-1-carboxamide(40 mg, 0.10 mmol) in tetrahydrofuran (10 mL), trifluoracetic anhydride(105 mg, 0.50 mmol) and triethylamine (60.6 mg, 0.60 mmol) were added.The reaction solution was then stirred overnight at room temperature.The reaction was then quenched with water (20 mL) and extracted withethyl acetate (100 ml). The combined organic layers were washed withbrine, dried over anhydrous magnesium sulfate and concentrated in vacuo.The residue was purified by Prep-HPLC to afford2-(7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)cyclopropane-1-carbonitrileas a off-white solid (5.4 mg, 14%). LCMS (ESI): M+H⁺=383.0; ¹H NMR (400MHz, CD₃OD) 6.94-6.90 (m, 2H), 6.69-6.56 (m, 2H), 6.11 (s, 1H), 4.34 (s,2H), 3.56-3.51 (m, 2H), 2.94-2.90 (m, 1H), 1.99-1.94 (m, 1H), 1.80-1.76(m, 1H), 1.60-1.55 (m, 1H), 1.25-1.21 (m, 3H)

Method 15 Example 15.1:7-((5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

Step 1: 1,1,1-trifluorohexane-2,4-dione

To a solution of ethyl 2,2,2-trifluoroacetate (4.20 g, 29.6 mmol) intetrahydrofuran (120 mL) was added (tert-butoxy)potassium (2.70 g, 24.1mmol), butan-2-one (1.44 g, 20.0 mmol). The resulting solution wasstirred for 12 h at room temperature. The reaction was then quenched bywater, extracted with ethyl acetate (3×100 mL), washed with brine, driedover anhydrous magnesium sulfate and concentrated under vacuum to afford1,1,1-trifluorohexane-2,4-dione (600 mg, 18%) as a yellow solid. Thecrude product was used in next step without further purification.

Step 2: 5-ethyl-3-(trifluoromethyl)-1H-pyrazole

To a solution of 1,1,1-trifluorohexane-2,4-dione (350 mg, 2.08 mmol) inethanol (20 mL) was added hydrazine monohydrate (135 mg, 2.19 mmol). Theresulting solution was stirred for 12 h at 80° C. in an oil bath. Theresulting mixture was concentrated under vacuum. The residue waspurified by chromatography with dichloromethane/methanol (100:1) toafford 5-ethyl-3-(trifluoromethyl)-1H-pyrazole (140 mg, 41%) as anoff-white solid.

Step 3:3-bromo-7-((5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-bromo-7-(chloromethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(from Example 4.1, Step 6) (165 mg, 0.56 mmol) in CH₃CN (20 mL) wasadded potassium iodide (46 mg, 0.28 mmol), potassium carbonate (155 mg,1.12 mmol) and 5-ethyl-3-(trifluoromethyl)-1H-pyrazole (110 mg, 0.67mmol). The resulting solution was stirred for 12 h at 80° C. in an oilbath. The resulting mixture was quenched with water (10 mL), extractedwith dichloromethane (3×20 mL), washed with brine, dried over anhydroussodium sulfate and concentrated under vacuum. The residue was purifiedby silica gel chromatography with ethyl acetate/petroleum ether (1:2.5)to afford3-bromo-7-[[5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(150 mg, 63%) as a light yellow solid.

Step 4: ethyl2-(7-((5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)cyclopropanecarboxylate

To a solution of3-bromo-7-[[5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(from Example 4.8, Step 1) (160 mg, 0.38 mmol) in CH₃CN (2 mL) was addedpotassium carbonate (166 mg, 1.20 mmol),[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride (30 mg,0.04 mmol), ethyl2-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)cyclopropane-1-carboxylate (184mg, 0.76 mmol) and water (0.6 mL). The reaction mixture was irradiatedin a microwave for 1 h at 120° C. The resulting mixture was quenchedwith water (10 mL), extracted with dichloromethane (3×20 mL), washedwith brine, dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified by chromatography with ethylacetate/petroleum ether (1:2) to afford2-(7-[[5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)cyclopropane-1-carboxylate(50 mg, 29%) as an off-white solid.

Step 5:2-(7-((5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)cyclopropanecarboxylicacid

To a solution of2-(7-[[5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)cyclopropane-1-carboxylate(50 mg, 0.11 mmol) in tetrahydrofuran (15 mL) was added a solution oflithium hydroxide (8 mg, 0.33 mmol) in water (1 mL). The resultingsolution was stirred for 12 h at room temperature. The pH value of thesolution was adjusted to pH 5 with aqueous hydrochloric acid. Theresulting solution was extracted with 3×20 mL of ethyl acetate, washedwith brine, dried over anhydrous magnesium sulfate, and concentratedunder vacuum to afford2-(7-[[5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)cyclopropane-1-carboxylicacid (40 mg, crude) as a reddish solid.

Step 6:7-((5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of2-(7-[[5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)cyclopropane-1-carboxylicacid (30 mg, 0.07 mmol) in tetrahydrofuran (10 mL) was addedtriethylamine (14 mg, 0.14 mmol) and chloro(propan-2-yloxy)methanone (17mg, 0.14 mmol). The resulting solution was stirred for 2 h at roomtemperature. Then a solution of sodium borohydride (8 mg, 0.21 mmol) inwater (0.5 mL) was added. The resulting solution was stirred for 12 h atroom temperature. The reaction was then quenched by the addition ofsaturated ammonium chloride aqueous solution, extracted withdichloromethane (3×20 mL), washed with brine, dried over anhydrousmagnesium sulfate and concentrated under vacuum. The residue waspurified by chromatorgraphy with ethyl acetate/petroleum ether (1:1.5)to afford7-[[5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(9.4 mg, 32%) as a light yellow solid. LCMS (ESI): [M+1]⁺413.1; ¹H NMR(300 MHz, CD₃OD) δ 6.51 (s, 1H), 5.67 (s, 1H), 5.25 (s, 2H), 3.64-3.54(m, 2H), 2.77-2.69 (m, 2H), 2.42 (s, 3H), 2.15-2.11 (m, 1H), 1.45-1.29(m, 4H), 1.27-1.12 (m, 2H).

The following examples were prepared in a manner similar to Example15.1:

LCMS No. Structure/Name (M + H) ¹H NMR 15.2

  7-((3,5-bis(trifluoromethyl)-1H-pyrazol-1- yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H- thiazolo[3,2-a]pyrimidin-5-one453.20 ¹H NMR (300 MHz, CD₃OD) δ 7.30 (s, 1H), 5.84 (s, 1H), 5.48 (s,2H), 3.61-3.59 (m, 2H), 2.43 (s, 3H), 2.17-2.15 (m, 1H), 1.37-1.30 (m,1H), 1.05-0.99 (m, 2H) 15.3

  7-((3-chloro-5-methyl-1H-pyrazol-1- yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H- thiazolo[3,2-a]pyrimidin-5-one365.0 ¹H NMR (300 MHz, CDCl₃) δ 6.04 (s, 1H), 5.67 (s, 1H), 5.06 (s,2H), 4.06-4.01 (m, 1H), 3.14-3.06 (m, 1H), 2.39 (s, 3H), 2.25 (s, 4H),1.30-1.20 (m, 1H). 1.05-0.97 (m, 2H) 15.4

  7-((5-chloro-3-methyl-1H-pyrazol-1- yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H- thiazolo[3,2-a]pyrimidin-5-one365.0 ¹H NMR (300 MHz, CDCl₃) δ 6.10 (s, 1H), 5.61 (s, 1H), 5.15 (s,2H), 4.07-4.02 (m, 2H), 3.12-3.05 (m, 1H), 2.38 (s, 3H), 2.27 (s, 3H),2.23 (s, 1H), 1.30-1.26 (m, 1H), 1.05-0.94 (m, 2H) 15.5

  3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-7-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-5H-thiazolo[3,2-a]pyrimidin-5- one 385 ¹H NMR (300 MHz,CDCl₃) δ 7.63-7.58 (m, 1H), 6.61-6.60 (m, 1H), 5.86 (s, 1H), 5.22 (s,2H), 4.05-4.00 (m, 1H), 3.15-3.08 (m, 1H), 2.38 (s, 3H), 2.29-2.24 (m,1H), 1.28-1.19 (m, 1H), 1.05- 0.95 (m, 2H). 15.6

  7-((1H-indazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H- thiazolo[3,2-a]pyrimidin-5-one367.1 ¹H NMR (300 MHz, CDCl₃) δ 8.09 (s, 1H), 7.79-7.76 (m, 1H),7.42-7.37 (m, 2H), 7.22-7.17 (m, 1H), 5.57 (s, 1H), 5.47 (s, 2H), 4.35(s, 2H), 3.07-3.04 (m, 1H), 2.37 (s, 3H), 2.23-2.21 (m, 1H), 1.25-1.21(m, 1H), 1.02-0.92 (m 2H)

Example 15.7 and 15.8:7-((5-(2-hydroxyethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-oneand7-((3-(2-hydroxyethyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

Step 1: ((but-3-ynyloxy)methyl)benzene

A mixture of but-3-yn-1-ol (3.0 g, 42.8 mmol), sodium hydride (3.0 g,125.0 mmol), (bromomethyl)benzene (7.2 g, 42.1 mmol) inN,N-dimethylformamide (10 mL) was stirred at room temperature overnight.The resulting mixture was extracted with dichloromethane, washed withbrine, washed with brine and concentrated under vacuum to afford crude[(but-3-yn-1-yloxy)methyl]benzene (2.6 g, 38%) as yellow oil. ¹H NMR(300 MHz, CDCl₃) δ 7.30-7.27 (m, 5H), 4.81 (s, 2H), 3.64-3.59 (m, 2H),2.55-2.49 (m, 2H), 2.02-2.00 (m, 1H).

Step 2: 6-(benzyloxy)-1,1,1-trifluorohex-3-yn-2-one

To a solution of [(but-3-yn-1-yloxy)methyl]benzene (1.00 g, 6.24 mmol)in tetrahydrofuran (20 mL) was added butyllithium (2.5 M in hexanes; 3.0mL, 7.50 mmol) dropwise at −78° C. The resulting solution was stirredfor 0.5 h at −78° C. and 2,2,2-trifluoroethyl 2,2,2-trifluoroacetate(1.47 g, 7.50 mmol), trifluoroborane etherate (1.15 g, 7.50 mmol) wasadded to the reaction mixture and stirred for further 3 h at −78° C. Theresulting mixture was washed with brine, extracted with dichloromethane(3×100 mL), washed with brine, dried over sodium sulfate andconcentrated under vacuum. The residue was purified by column yridineraphy with ethyl acetate/petroleum ether (1:100) to afford6-(benzyloxy)-1,1,1-trifluorohex-3-yn-2-one (0.6 g, 38%) as yellow oil.¹H NMR (300 MHz, CDCl₃) δ 7.40-7.27 (m, 5H), 4.58 (s, 2H), 3.72-3.68 (m,2H), 2.83-2.79 (m, 2H).

Step 3: 5-(2-(benzyloxy)ethyl)-3-(trifluoromethyl)-1H-pyrazole

A mixture of 6-(benzyloxy)-1,1,1-trifluorohex-3-yn-2-one (0.6 g, 2.34mmol) in hydrazine monohydrate (0.5 g, 10 mmol) and ethanol (10 mL) wasstirred at 85° C. for 3 h. The resulting mixture was extracted withdichloromethane (3×100 mL), washed with brine, dried over sodium sulfateand concentrated under vacuum to afford5-[2-(benzyloxy)ethyl]-3-(trifluoromethyl)-1H-pyrazole (0.6 g, 95%) as ayellow oil. ¹H NMR (300 MHz, CDCl₃) δ 7.40-7.29 (m, 5H), 6.32 (s, 1H),4.57 (s, 2H), 3.76-3.72 (m, 2H), 2.96-2.92 (m, 2H).

Step 4: 2-(3-(trifluoromethyl)-1H-pyrazol-5-yl)ethanol

A mixture of 5-[2-(benzyloxy)ethyl]-3-(trifluoromethyl)-1H-pyrazole (400mg, 1.48 mmol), palladium on carbon (150 mg), O-(hydroxychloryl)oxidanol(0.01 mL) in methanol (15 mL) and tetrahydrofuran (4 mL) was stirred atroom temperature for 70 min under hydrogen. The solids were filtered offand the resulting mixture was concentrated under vacuum to afford2-[3-(trifluoromethyl)-1H-pyrazol-5-yl]ethan-1-ol (250 mg, 95%) as abrown solid. LCMS [M+H]⁺=181.0.

Step 5:3-bromo-7-((5-(2-hydroxyethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-oneand3-bromo-7-((3-(2-hydroxyethyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

A mixture of 2-(3-(trifluoromethyl)-1H-pyrazol-5-yl)ethan-1-ol (480 mg,2.66 mmol),3-bromo-7-(chloromethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(from Example 4.1, Step 6) (300 mg, 1.02 mmol), potassium carbonate (690mg, 4.99 mmol), and potassium iodide (0.28 g, 1.70 mmol) in CH₃CN (15mL) was stirred at 85° C. for 2 h. The resulting mixture was extractedwith dichloromethane (3×100 mL), washed with brine, dried over sodiumsulfate and concentrated under vacuum. The residue was purified bysilica gel column chromatography with ethyl acetate/petroleum ether(1:2) to afford a mixture of3-bromo-7-[[5-(2-hydroxyethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneand3-bromo-7-((3-(2-hydroxyethyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(470 mg, 40%) as a light yellow solid. LCMS (ESI): [M+H]⁺=437.0, 439.0.

Step 6:7-((5-(2-hydroxyethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-oneand7-((3-(2-hydroxyethyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

A mixture of3-bromo-7-[[5-(2-hydroxyethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(200 mg, 0.46 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride (35 mg, 0.05 mmol), sodium carbonate (100 mg, 0.94 mmol),potassium trans-2-(hydroxymethyl)cyclopropyltrifluoroborate (fromExample 4.1, Step 2) (160 mg, 0.90 mmol) in CH₃CN (6 mL) and H₂O (2 mL)was irradiated with microwave radiation for 1.5 h at 120° C. in asealed-tube. The resulting mixture was extracted with dichloromethane(3×20 mL), washed with brine, dried over sodium sulfate and concentratedunder vacuum. The residue was purified by Prep-HPLC (Xselect CSH PrepC18 OBD Column, 5 um, 19×150 mm; mobile phase, water with 0.03% NH₃—H₂Oand MeCN (23.0% MeCN up to 28.0% in 20 min)) to afford7-[[5-(2-hydroxyethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(19.7 mg, 10.2%) as a white solid and7-((3-(2-hydroxyethyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(4.3 mg, 2.2%).

Example 15.7

7-[[5-(2-hydroxyethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one.LCMS (ESI): [M+H]⁺=429.1; ¹H NMR (300 MHz, CDCl₃) δ 6.46 (s, 1H), 5.81(s, 1H), 5.24 (s, 2H), 4.04-3.93 (m, 1H), 3.91-3.89 (m, 2H), 3.13-3.06(m, 1H), 2.94-2.90 (m, 4H), 2.38 (s, 3H), 2.27-2.21 (m, 1H), 1.27-1.16(m, 1H), 1.01-0.90 (m, 2H).

Example 15.8

7-((3-(2-hydroxyethyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one.LCMS (ESI): [M+H]⁺=429.0; ¹H NMR (300 MHz, CDCl₃) δ 6.91 (s, 1H), 5.56(s, 1H), 5.26 (s, 2H), 4.06-4.01 (m, 1H), 3.96-3.92 (m, 2H), 3.12-3.06(m, 1H), 2.94-2.89 (m, 2H), 2.38 (s, 3H), 2.21-2.15 (m, 1H), 1.27-1.16(m, 1H), 1.03-0.90 (m, 2H).

Example 15.9 and 15.10:7-((3-cyclopropyl-4-fluoro-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-oneand7-((5-cyclopropyl-4-fluoro-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

Step 1: 1-cyclopropyl-4,4,4-trifluorobutane-1,3-dione

A mixture of sodium metal (276 mg, 12.0 mmol) and ethanol (20 mL) wasstirred for 20 minutes at room temperature. To the reaction mixture wasadded 1-cyclopropylethan-1-one (1.42 mg, 0.0200 mmol) and ethyl2,2,2-trifluoroacetate (840 mg, 5.91 mmol) and the resulting solutionwas stirred for 2 days at room temperature. The reaction was quenchedwith water (50 mL), extracted with dichloromethane (3×20 mL) washed withbrine, and dried over anhydrous sodium sulfate and concentrated undervacuum to afford 1-cyclopropyl-4,4,4-trifluorobutane-1,3-dione (737 mg,69%) as colorless oil. The crude product was used in next step withoutfurther purification.

Step 2: 3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazole

To a solution of 1-cyclopropyl-4,4,4-trifluorobutane-1,3-dione (400 mg,2.22 mmol) in ethanol (20 mL) was added hydrazine monohydrate (132 mg,excess) and the resulting solution was stirred for 2 days at 80° C. Theresulting mixture was concentrated under vacuum. The residue waspurified by chromatography with 2% methanol in dichloromethane to afford3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazole (258 mg, 66%) as anoff-white solid. LCMS (ESI): [M+H]⁺=177.0; ¹H NMR (300 MHz, CDCl₃) δ6.27 (s, 1H), 2.08-1.95 (m, 1H), 2.77-2.64 (m, 2H), 1.11-1.02 (m, 2H).

Step 3: 5-cyclopropyl-4-fluoro-3-(trifluoromethyl)-1H-pyrazole

To a solution of 5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazole (500 mg,2.84 mmol) in CH₃CN (10 mL) maintained with an inert atmosphere ofnitrogen was added Selectfluor® (1.0 g, 2.84 mmol). The resultingsolution was stirred for 12 h at 75° C. The resulting mixture was thenconcentrated under vacuum. The residue was purified by chromatographywith 1% methanol in dichloromethane to afford5-cyclopropyl-4-fluoro-3-(trifluoromethyl)-1H-pyrazole (280 mg, 51%) asa yellow solid. LCMS (ESI): [M+H]⁺=195.0; ¹H NMR (300 MHz, CDCl₃) δ 1.81(m, 1H), 1.03 (m, 2H), 0.85 (m, 2H).

Step 4:3-bromo-7-((3-cyclopropyl-4-fluoro-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-oneand3-bromo-7-((5-cyclopropyl-4-fluoro-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-bromo-7-(chloromethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(from Example 4.1, Step 6) (250 mg, 0.85 mmol) in CH₃CN (20 mL) wasadded 5-cyclopropyl-4-fluoro-3-(trifluoromethyl)-1H-pyrazole (200 mg,1.03 mmol), potassium iodide (80 mg, 0.42 mmol), potassium carbonate(250 mg, 1.81 mmol). The resulting solution was stirred for 12 h at 80°C. The resulting mixture was concentrated under vacuum. The residue waspurified by chromatography with ethyl acetate/petroleum ether (1:3) toafford3-bromo-7-[[3-cyclopropyl-4-fluoro-5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(100 mg, 20%) as a light yellow solid (LCMS (ESI): [M+H]⁺=452.2) and3-bromo-7-[[5-cyclopropyl-4-fluoro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(200 mg, 50%) as a light yellow solid (LCMS (ESI): [M+1]⁺=452.0).

Step 5:7-((3-cyclopropyl-4-fluoro-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(Example 15.9)

To a solution of3-bromo-7-[[3-cyclopropyl-4-fluoro-5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(90 mg, 0.20 mmol) in CH₃CN (2 mL) under nitrogen, was added sodiumcarbonate (43 mg, 0.41 mmol),[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (30 mg,0.04 mmol), potassium trans-2-(hydroxymethyl)cyclopropyltrifluoroborate(from Example 4.1, Step 2) (140 mg, 0.79 mmol) and water (0.6 mL). Thereaction mixture was heated under microwave irradiation for 90 min at120° C. The reaction mixture was then quenched with water (10 mL),extracted with ethyl acetate (3×20 mL), washed with brine, dried overanhydrous magnesium sulfate and concentrated under vacuum. The residuewas purified on a silica gel column with ethyl acetate/petroleum ether(1:1), afford7-[[3-cyclopropyl-4-fluoro-5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(10.5 mg, 12%) as a light yellow solid. LCMS (ESI): [M+H]⁺=442.9; ¹H NMR(300 MHz, CD₃OD) δ 5.65 (s, 1H), 5.18 (s, 1H), 5.21 (s, 2H), 3.59 (m,2H), 2.48 (s, 3H), 2.18 (m,1H), 1.90 (m, 1H), 1.34 (m, 2H), 0.98 (m,3H), 0.84 (m, 2H).

Step 6:7-((5-cyclopropyl-4-fluoro-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(Example 15.10)

Into a 10-mL sealed tube purged and maintained with an inert atmosphereof nitrogen, was placed3-bromo-7-[[5-cyclopropyl-4-fluoro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(100 mg, 0.22 mmol), acetonitrile (2 mL),[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (34 mg,0.05 mmol), sodium carbonate (48 mg, 0.45 mmol), potassiumtrans-2-(hydroxymethyl)cyclopropyltrifluoroborate (from Example 4.1,Step 2) (153 mg, 0.86 mmol) and water (0.6 mL). The reaction mixture wasirradiated with microwave radiation for 90 min at 120° C. The resultingsolution was extracted with ethyl acetate (3×20 mL), washed with brine,dried over anhydrous magnesium sulfate and concentrated in vacuo. Theresidue was purified by chromatography with ethyl acetate/petroleumether (1:1), to afford7-[[5-cyclopropyl-4-fluoro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(18.5 mg, 19%) as a off-white solid. LCMS (ESI): [M+H]⁺=443.0; ¹H NMR(300 MHz, CD₃OD) δ 5.85 (s, 1H), 5.38 (s, 2H), 3.65 (m, 2H), 2.43 (s,3H), 2.12 (m, 1H), 1.80 (m, 1H), 1.32 (m, 2H), 0.99 (m, 4H), 0.85 (m,2H).

The following examples were prepared in a manner similar to Example15.7-15.10:

LCMS No. Structure/Name (M + H) ¹H NMR 15.11

  7-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H- thiazolo[3,2-a]pyrimidin-5-one425.25 ¹H NMR (300 MHz, CDCl₃) δ 6.35 (s, 1H), 5.54 (s, 1H), 5.22 (s,2H), 4.06-4.02 (m, 2H), 3.12-3.05 (m, 1H), 2.38 (s, 3H), 2.26-2.22 (m,1H), 2.00-1.91 (m, 1H), 1.32-1.21 (m, 1H), 1.05- 0.92 (m, 4H), 0.83-0.74(m, 2H) 15.12

  7-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H- thiazolo[3,2-a]pyrimidin-5-one425.0 ¹H NMR (300 MHz, CDCl₃) δ 6.19 (s, 1H), 5.67 (s, 1H), 5.32 (s,2H), 4.06-4.01 (m, 1H), 3.14- 3.07 (m, 1H), 2.41 (s, 3H), 2.29- 2.23 (m,1H), 1.74-1.66 (m, 1H), 1.28-1.23 (m, 1H), 1.06-0.95 (m, 4H), 0.78-0.69(m, 2H)

Examples 15.13, 15.14, 15.15, and 15.16:7-[(5-cyclopropyl-3-methyl-pyrazol-1-yl)methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one(Enantiomers 1 and 2) and7-[(3-cyclopropyl-5-methyl-pyrazol-1-yl)methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one(Enantiomers 1 and 2)

Examples 15.13, 15.14, 15.15 and 15.16 were prepared in a manneranalogous to 15.7, where2-[3-(trifluoromethyl)-1H-pyrazol-5-yl]ethan-1-ol was replaced by5-cyclopropyl-3-methyl-1H-pyrazole in Step 5. Following thecross-coupling procedure in Step 6, the crude product was purified byPrep-HPLC (Column, XBridge Prep C18 OBD Column, 19*150 mm, 5 um; mobilephase, CH₃CN and water with 0.5% NH₃H₂O (35% CH₃CN up to 45% in 10mins); Detector, UV 254/220 nm) to afford a mixture of racemic7-[(5-cyclopropyl-3-methyl-pyrazol-1-yl)methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-oneand racemic7-[(3-cyclopropyl-5-methyl-pyrazol-1-yl)methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one(60 mg, 70%) as a white solid. This material was purified by Chiral-HPLC(Column, CHIRALCEL, OJ-H (2×25 cm, 5 um); mobile phase, Hex:EtOH=85:15,25 mins, flow rate, 20 ml/min; Detector, UV 254/220 nm) to afford fourisomers:

Example 15.13

7-[(5-cyclopropyl-3-methyl-pyrazol-1-yl)methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one(peak 1, enantiomer 1). Retention time=8.2 min; Yield=4.2 mg, 5.0%; LCMS(ESI): M+H⁺=271.1; ¹H NMR (300 MHz, CDCl₃) δ 5.75 (s, 1H), 5.68 (s, 1H),5.31 (s, 2H), 4.06-3.98 (m, 2H), 3.15-3.03 (m, 1H), 2.37 (s, 3H),2.28-2.20 (m, 4H), 1.63-1.57 (m, 1H), 1.23-1.13 (m, 1H), 1.02-0.83 (m,4H), 0.70-0.61 (m, 2H).

Example 15.14

7-[(5-cyclopropyl-3-methyl-pyrazol-1-yl)methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one(peak 2, enantiomer 2). Retention time=10 min; Yield=2.8 mg, 3.3%; LCMS(ESI): M+H⁺=271.1; ¹H NMR (300 MHz, CDCl₃) δ 5.75 (s, 1H), 5.68 (s, 1H),5.31 (s, 2H), 4.06-3.98 (m, 2H), 3.15-3.03 (m, 1H), 2.37 (s, 3H),2.28-2.20 (m, 4H), 1.63-1.57 (m, 1H), 1.23-1.13 (m, 1H), 1.02-0.83 (m,4H), 0.70-0.61 (m, 2H).

Example 15.15

7-[(3-cyclopropyl-5-methyl-pyrazol-1-yl)methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one(peak 3, enantiomer 1). Retention time=14.8 min; Yield=6.9 mg, 8.2%;LCMS (ESI): M+H⁺=271.1; ¹H NMR (300 MHz, CDCl₃) δ 5.75 (s, 1H), 5.57 (s,1H), 5.08 (s, 2H), 4.04-4.00 (m, 2H), 3.12-3.05 (m, 1H), 2.37 (s, 3H),2.28-2.19 (m, 4H), 1.94-1.86 (m, 1H), 1.23-1.11 (m, 1H), 1.02-0.86 (m,4H), 0.71-0.63 (m, 2H).

Example 15.16

7-[(3-cyclopropyl-5-methyl-pyrazol-1-yl)methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one(peak 4, enantiomer 2). Retention time=17.6 min; Yield=14.6 mg, 17.4%;LCMS (ESI): M+H⁺=271.1; ¹H NMR (300 MHz, CDCl₃) δ 5.75 (s, 1H), 5.57 (s,1H), 5.08 (s, 2H), 4.04-4.00 (m, 2H), 3.12-3.05 (m, 1H), 2.37 (s, 3H),2.28-2.19 (m, 4H), 1.94-1.86 (m, 1H), 1.23-1.11 (m, 1H), 1.02-0.86 (m,4H), 0.71-0.63 (m, 2H).

The following examples were prepared in a manner similar to thepreceding examples:

LCMS No. Structure/Name (M + H) ¹H NMR 15.17

  7-[(3,5-dicyclopropylpyrazol-1-yl)methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 397.1 ¹H NMR (300 MHz, CDCl₃) δ5.62 (s, 1H), 5.55 (s, 1H), 5.18 (s, 2H), 4.06-3.98 (m, 2H), 3.12- 3.01(m, 1H), 2.37 (s, 3H), 2.28- 2.15 (m, 1H), 1.89-1.80 (m, 1H), 1.60-1.49(m, 2H), 1.26-1.13 (m, 2H), 1.02-0.80 (m, 5H), 0.71- 0.53 (m, 3H) 15.18

  7-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-6-fluoro-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 363.0 ¹H NMR (300 MHz, CDCl₃)δ 5.85 (s, 1H), 5.22-5.19 (m, 2H), 4.09-4.00 (m, 1H), 3.77-3.74 (m, 1H),3.25-3.18 (m, 1H), 2.38 (s, 3H), 2.31 (s, 3H), 2.29-2.27 (m, 1H), 2.23(s, 3H), 1.32-1.28 (m, 1H), 1.08-1.01 (m, 2H). 15.19

  1-((3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-5- carbonitrile 410.0 ¹H NMR(300 MHz, CDCl₃) δ 7.12 (s, 2H), 5.93 (s, 1H), 5.39 (s, 2H), 4.06-4.01(m, 1H), 3.15-3.08 (m, 1H), 2.39 (s, 3H), 2.39-2.23 (m, 1H), 1.33-1.22(m, 1H), 1.05-1.02 (m, 2H) 15.20

  7-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-6-fluoro-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H- thiazolo[3,2-a]pyrimidin-5-one443.0 ¹H NMR (300 MHz, CD₃OD) δ 6.29 (s, 1H), 5.53 (s, 2H), 3.71- 3.57(m, 2H), 2.41 (s, 3H), 2.17- 2.15 (m, 1H), 2.01-1.94 (m, 1H), 1.46-1.41(m, 1H), 1.09-1.01 (m, 4H), 0.77-0.72 (m, 2H). 15.21

  1-[[3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl]methyl]-5-methyl-pyrazole-3-carbonitrile 356.1 ¹H NMR (400 MHz,DMSO-d₆) δ 6.81 (s, 1H), 5.70 (s, 1H), 5.29 (s, 2H), 4.53 (s, 1H), 3.46(d, J = 5.9 Hz, 2H), 2.36 (d, J = 1.5 Hz, 3H), 2.32 (s, 3H), 2.00 (dtd,J = 7.1, 5.4, 1.7 Hz, 1H). 1.27 (dp, J = 8.5, 5.8 Hz, 1H), 0.85 (ddt, J= 16.0, 8.6, 5.1 Hz, 2H). 15.22

  7-[[3-(difluoromethyl)-5-methyl-pyrazol-1- yl]methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl- thiazolo[3,2-a]pyrimidin-5-one381.1 ¹H NMR (400 MHz, DMSO-d₆) δ 6.91 (t, J = 54.9 Hz, 1H), 6.38 (s,1H), 5.52 (s, 1H), 5.19 (s, 2H), 4.52 (t, J = 5.7 Hz, 1H), 3.45 (t, J =5.8 Hz, 2H), 2.36 (d, J = 1.5 Hz, 3H), 2.30 (s, 3H), 2.05-1.91 (m, 1H),1.27 (dt, J = 8.7, 5.6 Hz, 1H), 0.97-0.66 (m, 3H). 15.23

  7-[(6-fluoroindazol-1-yl)methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl- thiazolo[3,2-a]pyrimidin-5-one385.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.18 (s, 1H), 7.85 (dd, J = 8.9, 5.2Hz, 1H), 7.59 (dd, J = 9.8, 2.2 Hz, 1H), 7.10-7.00 (m, 1H), 5.50 (s,2H), 5.47 (s, 1H), 4.50 (t, J = 5.5 Hz, 1H), 3.43 (t, J = 5.7 Hz, 2H),2.35 (d, J = 1.8 Hz, 3H), 2.04-1.89 (m, 1H), 1.25 (dp, J = 9.0, 5.9 Hz,1H), 0.82 (ddt, J = 15.2, 8.6, 5.0 Hz, 2H). 15.24

  7-[[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-isopropyl-thiazolo[3,2-a]pyrimidin-5-one 453.2 ¹H NMR (400 MHz,DMSO-d₆) δ 6.48 (s, 1H), 5.63 (s, 1H), 5.37 (s, 2H), 4.57 (t, J = 5.6Hz, 1H), 3.65 (p, J = 6.7 Hz, 1H), 3.55- 3.37 (m, 2H), 2.05-1.88 (m,2H), 1.28 (dq, J = 8.8, 5.6 Hz, 1H), 1.22 (d, J = 6.8 Hz, 6H), 1.01-0.91 (m, 2H), 0.91-0.85 (m, 1H), 0.81 (dt, J = 8.8, 5.2 Hz, 1H), 0.73(dt, J = 6.7, 4.0 Hz, 2H). 15.25

  7-[(3,5-dimethylpyrazol-1-yl)methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl- thiazolo[3,2-a]pyrimidin-5-one345.2 ¹H NMR (400 MHz, DMSO-d₆) δ 5.89 (s, 1H), 5.35 (s, 1H), 5.02 (s,2H), 4.52 (t, J = 5.6 Hz, 1H), 3.45 (t, J = 5.8 Hz, 2H), 2.36 (d, J =1.6 Hz, 3H), 2.19 (s, 3H), 2.10 (s, 3H), 2.00 (qd, J = 7.4, 6.5, 2.6 Hz,1H), 1.33-1.20 (m, 1H), 0.95-0.76 (m, 2H). 15.26

  7-[(5-fluoroindazol-1-yl)methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl- thiazolo[3,2-a]pyrimidin-5-one385.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.14 (s, 1H), 7.74 (dd, J = 9.1, 4.3Hz, 1H), 7.58 (dd, J = 9.2, 2.4 Hz, 1H), 7.31 (td, J = 9.2, 2.5 Hz, 1H),5.54 (s, 2H), 5.47 (s, 1H), 4.50 (t, J = 5.5 Hz, 1H), 3.43 (t, J = 5.5Hz, 2H), 2.35 (s, 3H), 1.97 (ddd, J = 9.6, 6.7, 4.8 Hz, 1H), 1.31-1.15(m, 1H), 0.82 (ddt, J = 16.2, 8.7, 5.1 Hz, 2H).

Example 15.27:5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-bromo-7-[[5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(from Example 15.1, Step 3) (80 mg, 0.19 mmol), 1,4-dioxane (2 mL),potassium phosphate (80 mg, 0.38 mmol),tetrakis(triphenylphosphine)palladium (22 mg, 0.02 mmol) and water (0.2mL) in 1,4-dioxane (2 mL) under nitrogen, was added(pyrimidin-5-yl)boronic acid (47 mg, 0.38 mmol). The resulting solutionwas stirred for 3 h at 90° C. in an oil bath. The resulting mixture wasquenched by water (10 mL), and extracted with dichloromethane (3×30 mL),washed with brine, dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was purified by chromatography with ethylacetate/petroleum ether (1:1) to afford7-[[5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-methyl-3-(pyrimidin-5-yl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(18.9 mg, 24%) as a yellow solid. LCMS (ESI): [M+H]⁺=462.0; ¹H NMR (300MHz, CD₃OD) δ 9.18 (s, 1H), 8.82 (s, 2H), 6.52 (s, 1H), 5.70 (s, 1H),5.31 (s, 2H), 2.80-2.72 (m, 2H), 2.30 (s, 3H), 1.34-1.29 (m, 3H).

Example 15.28 and 15.29:7-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-oneand7-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one

Step 1:3-bromo-7-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-oneand3-bromo-7-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-bromo-7-(chloromethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(from Example 4.1, Step 6) (373 mg, 1.27 mmol) in CH₃CN (10 mL) wasadded 3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazole (from Example 15.9,Step 2) (450 mg, 2.55 mmol), cesium carbonate (223 mg, 0.68 mmol) andpotassium iodide (160 mg). The resulting solution was stirred overnightat 80° C. The solids were filtered off and the resulting mixture wasconcentrated under vacuum. The crude product was purified by Prep-HPLC(Xbridge Shield RP18 OBD Column, 5 um, 19×150 mm; mobile phase, waterwith 0.03% NH₃H₂O and CH₃CN (10.0% CH₃CN up to 32.0% in 10 min, up to100.0% in 1 min, hold 100.0% in 1 min, down to 10.0% in 2 min);Detector, uv 254 nm) to afford3-bromo-7-[[3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(18 mg, 3%) as a white solid (LCMS (ESI): [M+H]⁺=434.9; ¹H NMR (300 MHz,CDCl₃) δ 6.36 (s, 1H), 5.54 (s, 1H), 5.21 (s, 2H), 2.35 (s, 3H),1.90-2.01 (m, 1H), 0.94-1.00 (m, 2H), 0.71-0.79 (m, 2H)) and3-bromo-7-[[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(54 mg, 10%) as a white solid (LCMS (ESI): [M+H]⁺=434.9; ¹H NMR (300MHz, CDCl₃) δ 6.18 (s, 1H), 5.66 (s, 1H), 5.30 (s, 2H), 2.36 (s, 3H),1.72-1.65 (m, 1H), 1.03-0.98 (m, 2H), 0.76-0.71 (m, 2H)).

Step 4:7-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one(Example 15.28)

To a solution of3-bromo-7-[[3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(12 mg, 0.03 mmol) in CH₃CN (1.5 mL) and water (0.5 mL) was added(pyrimidin-5-yl)boronic acid (7 mg, 0.060 mmol), potassium phosphate (12mg, 0.06 mmol) and tetrakis(triphenylphosphine)palladium (2.0 mg, 10mmol %). After stirring 1 h at 100° C. under nitrogen atmosphere, theresulting mixture was concentrated under vacuum. The residue waspurified by silica gel chromatography with 1% methanol indichloromethane. The crude product was purified by Prep-HPLC (SunFirePrep C₁₈ OBD Column, 5 um, 19×150 mm; mobile phase, water with 10 mmolNH₄HCO₃ and CH₃CN (30.0% CH₃CN up to 60.0% in 8 min, up to 95.0% in 2min, down to 30.0% in 2 min); Detector, UV 254/220 nm) to afford7-[[3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-methyl-3-(pyrimidin-5-yl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(6.1 mg, 51%) as a white solid. LCMS (ESI): [M+H]⁺=433.2; ¹H NMR (300MHz, CDCl₃) δ 9.26 (s, 1H), 8.70 (s, 2H), 6.35 (s, 1H), 5.49 (s, 1H),5.26 (s, 2H), 2.29 (s, 3H), 1.98-1.88 (m, 1H), 0.99-0.93 (m, 2H),0.76-0.74 (m, 2H).

Step 5:7-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one(Example 15.29)

To a solution of3-bromo-7-[[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(33 mg, 0.08 mmol) in CH₃CN (1.5 mL) and water (0.5 mL) was added(pyrimidin-5-yl)boronic acid (21 mg, 0.17 mmol), potassium phosphate (35mg, 0.16 mmol) and tetrakis(triphenylphosphine)palladium (6 mg, 0.01mmol). After stirring 1 h at 100° C. under nitrogen atmosphere, theresulting mixture was concentrated under vacuum. The residue waspurified by chromatography with 1% methanol in dichloromethane. Thecrude product was purified by Prep-HPLC (SunFire Prep C₁₈ OBD Column, 5um, 19×150 mm; mobile phase, water with 10 mmol NH₄HCO₃ and CH₃CN (30.0%CH₃CN up to 60.0% in 8 min, up to 95.0% in 2 min, down to 30.0% in 2min); Detector, UV 254/220 nm) to afford7-[[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-methyl-3-(pyrimidin-5-yl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(29.2 mg, 89%) as a white solid. LCMS (ESI): [M+H]⁺=433.2; ¹H NMR (300MHz, CDCl₃) δ 9.26 (s, 1H), 8.70 (s, 2H), 6.18 (s, 1H), 5.64 (s, 1H),5.35 (s, 2H), 2.29 (s, 3H), 1.77-1.68 (m, 1H), 1.04-0.98 (m, 2H),0.75-0.70 (m, 2H).

The following examples were prepared in a manner similar to Example15.27, 15.28, and 15.29:

LCMS No. Structure/Name (M + H) ¹H NMR 15.30

461.10 ¹H NMR (300 MHz, DMSO- d₆) δ 9.19 (s, 1H), 8.85 (s, 2H), 7.69 (s,1H), 5.88 (s, 1H), 5.56 (s, 2H), 2.21 (s, 3H)7-((3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one 15.31

393 ¹H NMR (300 MHz, CDCl₃) δ 9.27 (s, 1H), 8.70 (s, 2H), 7.61-7.60 (m,1H), 6.61-6.60 (m, 1H), 5.84 (s, 1H), 5.25 (s, 2H), 2.28 (s, 3H)2-methyl-3-(pyrimidin-5-yl)-7-((5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-5H-thiazolo[3,2-a]pyrimidin-5-one 15.32

448.15 ¹H NMR (300 MHz, CDCl₃) δ 9.25 (s, 1H), 8.69 (s, 2H), 6.37 (s,1H), 5.61 (s, 1H), 5.20 (s, 2H), 2.33 (s, 3H), 2.29 (s, 3H)2-methyl-7-((5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one

The following compounds were prepared using methods analogous to thosedescribed above:

LCMS No. Structure/Name (M + H) ¹H NMR 15.33

382.95 ¹H NMR (300 MHz, CDCl₃) δ 8.85 (s, 1H), 7.69 (s, 1H), 5.88 (s,1H), 5.56 (s, 2H), 2.21 (s, 3H)7-((3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-5H-thiazolo[3,2- a]pyrimidin-5-one 15.34

375 ¹H NMR (300 MHz, CDCl₃) δ 9.22 (s, 1H), 8.65 (s, 2H), 8.08 (s, 1H),7.76 (m, 1H), 7.42-7.36 (m, 2H), 7.26-7.16 (m, 1H), 5.30 (s, 2H), 2.27(s, 3H) 7-((1H-indazol-1-yl)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin- 5-one

Method 16 Example 16.1 and 16.2:7-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-N,2-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamideand7-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-N,2-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

Step 1: ethyl 2-oxobutanoate

Into a 10 L 4-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen was placed diethyl oxalate (300 g, 2.05mol, 1.00 equiv) and tetrahydrofuran (4.4 L), followed by ethylmagnesium bromide (740 mL, 1.08 equiv) dropwise with stirring at −10° C.over 2 h. The resulting solution was stirred at −10° C. for 30 min andquenched by the addition of 500 mL 3 M hydrogen chloride. The pH valueof the solution was adjusted to pH 4 with hydrogen chloride (3 mol/L)and the resulting solution was extracted with 2×1 L of dichloromethane.The combined organic layers were washed with 1×2 L of sodium chloride,dried over anhydrous sodium sulfate and concentrated under vacuum toafford 200 g (crude) of ethyl 2-oxobutanoate as a yellow oil.

Step 2: ethyl 3-bromo-2-oxobutanoate

Into a 10-L 4-necked round-bottom flask was placed ethyl 2-oxobutanoate(265 g, 2.04 mol, 1.00 equiv), chloroform (5 L), a solution of HBr inAcOH (500 mL), and Br₂ (325 g, 2.03 mol, 1.00 equiv). The resultingsolution was stirred at 70° C. for 2 h, cooled to room temperature andconcentrated under vacuum to afford 392.9 g (92%) of ethyl3-bromo-2-oxobutanoate as a brown oil.

Step 3: ethyl 2-amino-5-methyl-1,3-thiazole-4-carboxylate

Into a 10-L round-bottom flask was placed ethyl 3-bromo-2-oxobutanoate(392.9 g, 1.88 mol, 1.00 equiv), 1,4-dioxane (3.5 L), and thiourea(143.8 g, 1.89 mol, 1.01 equiv). The resulting solution was stirredovernight at 100° C. and cooled to room temperature. The solids werethen collected by filtration, washed with Et₂O and dried under vacuum toafford 310 g (89%) of ethyl 2-amino-5-methyl-1,3-thiazole-4-carboxylateas a light brown solid.

Step 4: 2-amino-N,5-dimethyl-1,3-thiazole-4-carboxamide

Into a 1-L pressure tank reactor was placed ethyl2-amino-5-methyl-1,3-thiazole-4-carboxylate (140 g, 751.75 mmol, 1.00equiv) and 30% methylamine in EtOH (500 mL). The resulting solution wasstirred overnight at 85° C. and concentrated under vacuum. The residuewas purified on a silica gel column eluting withdichloromethane/methanol (20/1) to afford 80 g (62%) of2-amino-N,5-dimethyl-1,3-thiazole-4-carboxamide as a yellow solid.

Step 5:7-(chloromethyl)-N,2-dimethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide

Into a 3-L 3-necked round-bottom flask was placed2-amino-N,5-dimethyl-1,3-thiazole-4-carboxamide (80 g, 467.24 mmol, 1.00equiv), ethyl 4-chloro-3-oxobutanoate (154 g, 935.68 mmol, 2.00 equiv)and polyphosphoric acid (PPA) (800 g). The resulting solution wasstirred at 110° C. for 2 h, cooled to 80° C. and quenched by theaddition of 100 mL of water. The pH value of the solution was adjustedto pH 8 with sodium hydroxide (10% aq.). The solids were filtered offand the filtrate was extracted with dichloromethane (5 L×5). Thecombined organic layers were dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The residue was purified on a silica gelcolumn eluting with dichloromethane/methanol (20/1) to give 80 g (63%)of7-(chloromethyl)-N,2-dimethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamideas a tan solid. LCMS (ESI): [M+H]⁺=272; ¹H NMR (400 MHz, DMSO-d₆): δ8.38 (q, J=4.8 Hz, 1H), 6.39 (s, 1H), 4.60 (s, 2H), 2.74 (d, J=4.8 Hz,3H), 2.30 (s, 3H).

Step 6:7-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-N,2-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide(Example 16.1) and7-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-N,2-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide(Example 16.2)

To a solution of7-(chloromethyl)-N,2-dimethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(100 mg, 0.37 mmol), potassium iodide (30 mg, 0.19 mmol) and potassiumcarbonate (100 mg, 0.74 mmol) in CH₃CN (10 mL) was added5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazole (from Example 15.9, Step2) (80 mg, 0.45 mmol). The reaction mixture was stirred 3 h at 85° C. inan oil bath. After filtration to remove solids and concentration undervacuum, the residue was purified by silica gel chromatography with ethylacetate/petroleum ether (2:1) to afford7-[[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-N,2-dimethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(50.4 mg, 33%) as a white solid (LCMS (ESI): [M+H]⁺=412.0; ¹H NMR (300MHz, CDCl₃) δ 6.27 (bs, 1H), 6.19 (s, 1H), 5.64 (s, 1H), 5.32 (s, 2H),3.03 (m, 3H), 2.40 (s, 3H), 1.71-1.65 (m, 1H), 1.03-0.97 (m, 2H),0.76-0.66 (m, 2H)) and7-[[3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-N,2-dimethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(20.7 mg, 14%) as a white solid (LCMS (ESI): [M+H]⁺=411.9; ¹H NMR (300MHz, CDCl₃) δ 6.36 (s, 1H), 5.94 (br, 1H), 5.56 (s, 1H), 5.24 (s, 2H),3.03 (m, 3H), 2.42 (s, 3H), 1.98-1.89 (m, 1H), 0.99-0.91 (m, 2H),0.76-0.66 (m, 2H)).

Example 16.3 and 16.4:7-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-N-ethyl-5-oxo-2-(trifluoromethyl)-5H-thiazolo[3,2-a]pyrimidine-3-carboxamideand7-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-N-ethyl-5-oxo-2-(trifluoromethyl)-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

Step 1: methyl 2-amino-5-iodothiazole-4-carboxylate

To a solution of methyl 2-amino-1,3-thiazole-4-carboxylate (20 g, 0.13mol) in dichloromethane (300 mL) was added N-iodosuccinimide (34 g, 0.15mol) in portions. The resulting solution was stirred overnight at roomtemperature. Then the reaction mixture was washed with saturated aqueousNa₂SO₃ (3×150 mL). The organic layer was dried over anhydrous sodiumsulfate. After filtration, the filtrate was concentrated to affordmethyl 2-amino-5-iodo-1,3-thiazole-4-carboxylate (21 g, 58%) as areddish solid.

Step 2: methyl 5-iodothiazole-4-carboxylate

To a solution of methyl 2-amino-5-iodo-1,3-thiazole-4-carboxylate (21 g,0.074 mol) in tetrahydrofuran (400 mL) was added t-butylnitrite (11.5 g,0.11 mol). The resulting solution was stirred for 1 h at 50° C. in anoil bath. After cooled down to room temperature, the reaction mixturewas concentrated under vacuum. The residue was purified bychromatography with ethyl acetate/petroleum ether (1:5) to afford methyl5-iodo-1,3-thiazole-4-carboxylate (8 g, 40%) as a yellow solid. LCMS(ESI): [M+H]⁺=269.9; ¹H NMR (300 MHz, CDCl₃) δ 8.95 (s, 1H), 3.97 (s,3H).

Step 3: methyl 5-(trifluoromethyl)thiazole-4-carboxylate

To a solution of methyl 5-iodo-1,3-thiazole-4-carboxylate (8.00 g, 29.7mmol) and copper iodide (8.70 g, 45.7 mmol) in N,N-dimethylformamide(200 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (8.70g, 45.3 mmol). The resulting solution was stirred overnight at 80° C. inan oil bath. After filtration remove solids and concentration undervacuum, the residue was purified by chromatography with ethylacetate/petroleum ether (1:5) to afford methyl5-(trifluoromethyl)-1,3-thiazole-4-carboxylate (4 g, 64%) as a lightyellow solid. LCMS (ESI): [M+H]⁺=212.0; ¹H NMR (300 MHz, CDCl₃) δ 8.91(s, 1H), 4.00 (s, 3H).

Step 4: N-ethyl-5-(trifluoromethyl)thiazole-4-carboxamide

A mixture of methyl 5-(trifluoromethyl)-1,3-thiazole-4-carboxylate (1 g,4.74 mmol) and ethylamine in ethanol (10 mL) was placed in a 30-mLsealed tube. The resulting solution was stirred overnight at 50° C. inan oil bath. After concentration under vacuum, the residue was purifiedby chromatography with ethyl acetate/petroleum ether (1:5) to affordN-ethyl-5-(trifluoromethyl)-1,3-thiazole-4-carboxamide (400 mg, 38%) asa light yellow oil. LCMS (ESI): [M+H]⁺=225.0; ¹H NMR (300 MHz, CDCl₃) δ8.79 (s, 1H), 7.42 (br, 1H), 3.55-3.46 (m, 2H), 1.27 (m, 3H).

Step 5: 2-bromo-N-ethyl-5-(trifluoromethyl)thiazole-4-carboxamide

To a solution of N-ethyl-5-(trifluoromethyl)-1,3-thiazole-4-carboxamide(200 mg, 0.89 mmol) in tetrahydrofuran (3 mL) was added n-butyllithium(2.5 M in hexanes; 1.1 mL, 2.70 mmol) drop wise with stirring at −78° C.The resulting solution was stirred for 30 min at −78° C. Then carbontetrabromide (900 mg, 2.70 mmol) in tetrahydrofuran (5 mL) was addeddrop wise with stirring at −78° C. After stirred 1 h at −78° C., thereaction was quenched with water/ice, extracted with dichloromethane(2×30 mL), washed with brine, dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified by chromatography withethyl acetate/petroleum ether (1:10) to afford2-bromo-N-ethyl-5-(trifluoromethyl)-1,3-thiazole-4-carboxamide (40 mg,15%) as a light yellow solid. LCMS (ESI): [M+H]⁺=302.8, 304.8; ¹H NMR(300 MHz, CDCl₃) δ 3.53-3.44 (m, 2H), 1.27 (m, 3H).

Step 6: 2-amino-N-ethyl-5-(trifluoromethyl)thiazole-4-carboxamide

A mixture of2-bromo-N-ethyl-5-(trifluoromethyl)-1,3-thiazole-4-carboxamide (500 mg,1.65 mmol), 1,4-dioxane (5 mL) and ammonia (5 mL) was placed in a 30-mLsealed tube. The resulting solution was stirred overnight at 70° C. inan oil bath. The resulting mixture was extracted with CH₂Cl₂ (20 mL×2),washed with brine, dried over anhydrous sodium sulfate and concentratedin vacuo. The residue was purified by chromatography with ethylacetate/petroleum ether (1:1) to afford2-amino-N-ethyl-5-(trifluoromethyl)-1,3-thiazole-4-carboxamide (250 mg,63%) as a light yellow semi-solid. LCMS (ESI): [M+H]⁺=240.0; ¹H NMR (300MHz, CDCl₃) δ 7.15 (br, 1H), 5.24 (br, 2H), 3.48-3.39 (m, 2H), 1.22 (m,3H).

Step 7:7-(chloromethyl)-N-ethyl-5-oxo-2-(trifluoromethyl)-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

To a mixture of2-amino-N-ethyl-5-(trifluoromethyl)-1,3-thiazole-4-carboxamide (250 mg,1.05 mmol) and ethyl 4-chloro-3-oxobutanoate (350 mg, 2.13 mmol) wasadded polyphosphoric acid (5 g, excess). The resulting mixture wasstirred for 1.5 h at 110° C. in an oil bath. The reaction was thenquenched by the addition of water and the pH value of the solution wasadjusted to pH 8 with aqueous sodium hydroxide. The resulting mixturewas extracted with dichloromethane (100 mL×2), washed with brine, driedover anhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by silica gel chromatography with dichloromethane/ethyl acetate(10:1) to afford7-(chloromethyl)-N-ethyl-5-oxo-2-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(200 mg, 56%) as a white solid. LCMS (ESI): [M+H]⁺=339.9; ¹H NMR (300MHz, CDCl₃) δ 6.49 (s, 1H), 5.90 (br, 1H), 4.41 (s, 2H), 3.60-3.51 (m,2H), 1.22 (m, 3H).

Step 8:7-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-N-ethyl-5-oxo-2-(trifluoromethyl)-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide(Example 16.3) and7-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-N-ethyl-5-oxo-2-(trifluoromethyl)-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide(Example 16.4)

To a solution of7-(chloromethyl)-N-ethyl-5-oxo-2-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and potassium carbonate (80 mg, 2.00 equiv) inacetonitrile (8 mL) was added5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazole (from Example 15.9, Step2) (50 mg, 0.28 mmol). The resulting solution was stirred for 3 h at 80°C. in an oil bath. After filtration to remove solids and concentrationunder vacuum, the residue was purified by chromatography with ethylacetate/petroleum ether (1:2) to afford7-[[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-N-ethyl-5-oxo-2-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(26.3 mg, 23%) as a white solid (LCMS (ESI): [M+H]⁺=480.0; ¹H NMR (300MHz, CDCl₃) δ 6.20 (s, 1H), 5.89 (bs, 1H), 5.77 (s, 1H), 5.35 (s, 2H),3.59-3.50 (m, 2H), 1.73-1.61 (m, 1H), 1.22 (m, 3H), 1.07-1.00 (m, 2H),0.76-0.70 (m, 2H)) and7-[[3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-N-ethyl-5-oxo-2-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(16.5 mg, 15%) as a white solid (LCMS (ESI): [M+H]⁺=480.0; ¹H NMR (300MHz, CDCl₃) δ 6.38 (s, 1H), 5.84 (bs, 1H), 5.67 (s, 1H), 5.25 (s, 2H),3.59-3.50 (m, 2H), 1.98-1.89 (m, 1H), 1.22 (m, 3H), 0.99-0.91 (m, 2H),0.78-0.73 (m, 2H)).

The following example was prepared in a manner similar to Examples 16.1,16.2, 16.3, and 16.4:

LCMS No. Structure/Name (M + H) ¹H NMR 16.5

412.20 ¹H NMR (300 MHz, CDCl₃) δ 9.36 (br, 1H), 7.97 (s, 1H), 6.19 (s,1H), 5.80 (s, 1H), 5.37 (s, 2H), 3.49-3.40 (m, 2H), 1.75-1.66 (m, 1H),1.26- 1.20 (m, 3H), 1.02-0.95 (m, 2H), 0.74-0.65 (m, 2H)7-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-N-ethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

The following compounds were prepared using methods analogous to thosedescribed above:

LCMS No. Structure/Name (M + H) ¹H NMR 16.6

452.0 ¹H NMR (300 MHz, CDCl₃) δ 6.17 (s, 1H), 5.98 (s, 1H), 5.65 (s,1H), 5.31 (s, 2H), 3.57-3.48 (m, 2H), 2.18-2.11 (m, 1H), 1.69-1.62 (m,1H), 1.30-1.22 (m, 3H), 1.19-1.13 (m, 2H), 1.01-0.92 (m, 2H), 0.87- 0.81(m, 2H), 0.72-0.67 (m, 2H) 2-cyclopropyl-7-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-N-ethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine- 3-carboxamide 16.7

452.0 ¹H NMR (300 MHz, CDCl₃) δ 6.34 (s, 1H), 5.84 (s, 1H), 5.54 (s,1H), 5.21 (s, 2H), 3.57-3.49 (m, 2H), 2.20-2.13 (m, 1H), 1.96-1.89 (m,1H), 1.30-1.25 (m, 3H), 1.19-1.12 (m, 2H), 0.98-0.90 (m, 2H), 0.87- 0.81(m, 2H), 0.79-0.71 (m, 2H) 2-cyclopropyl-7-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-N-ethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine- 3-carboxamide

Method 17 Example 17.1:2-methyl-5-oxo-7-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile

Step 1:3-bromo-2-methyl-7-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-bromo-7-(chloromethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(from Example 4.1, Step 6) (300 mg, 0.76 mmol) in CH₃CN (5 mL) was added3-(trifluoromethyl)-1H-pyrazole (125 mg, 0.92 mmol), potassium carbonate(316 mg, 2.29 mmol) and potassium iodide (63 mg, 0.38 mmol). Theresulting solution was heated to reflux overnight. The solids werefiltered out and the filtrate was concentrated under vacuum. The residuewas purified by silica gel chromatography with dichloromethane/methanol(50/1) to afford3-bromo-2-methyl-7-[[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(200 mg, 67%) as a white solid.

Step 2:2-methyl-5-oxo-7-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile

To a solution of3-bromo-2-methyl-7-[[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(120 mg, 0.31 mmol) in N,N-dimethylformamide (2 mL) was added copper (I)cyanide (32 mg, 0.36 mmol). The resulting solution was stirred for 1 hat 100° C. The reaction was then quenched by the addition of water. Thesolids were filtered off and the filtrate was extracted with ethylacetate (3×10 mL), washed with brine, dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was purified bychromatography with ethyl acetate/petroleum ether (1/5) to afford2-methyl-5-oxo-7-[[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carbonitrile(10.2 mg, 10%) as a white solid. LCMS (ESI): [M+H]⁺=340; ¹H NMR (300MHz, CDCl₃) δ 7.59 (m, 1H), 6.62 (m, 1H), 5.99 (s, 1H), 5.24 (s, 2H),2.67 (s, 3H).

The following examples were prepared in a manner similar to Example17.1:

LCMS No. Structure/Name (M + H) ¹H NMR 17.2

380.0  ¹H NMR (300 MHz, CD₃OD) δ 6.34 (s, 1H), 5.89 (s, 1H), 5.44 (s,2H), 2.66 (s, 3H), 1.91 (m, 1H), 1.04 (m, 2H), 0.77 (m, 2H)7-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile 17.3

379.90 ¹H NMR (300 MHz, CD₃OD) δ 6.57 (s, 1H), 5.71 (s, 1H), 5.30 (s,2H), 2.64 (s, 3H), 1.95 (m, 1H), 0.96 (m, 2H), 0.75 (m, 2H)7-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile

Method 18 Example 18.1:3-(1-hydroxyethyl)-2-methyl-7-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-5H-thiazolo[3,2-a]pyrimidin-5-one

Step 1: 4-bromopentane-2,3-dione

To a solution of pentane-2,3-dione (1.00 g, 9.99 mmol) in chloroform (30mL) was added bromine (1.60 g, 10.01 mmol) and hydrogen bromide inacetic acid (33 wt %; 3 drops). The resulting solution was stirred for 3h at 50° C. The resulting solution was concentrated to afford4-bromopentane-2,3-dione as a solid (1.79 g). The crude product was usedin next step without further purification.

Step 2: 1-(2-amino-5-methylthiazol-4-yl)ethanone

To a solution of 4-bromopentane-2,3-dione (1.79 g, 10.00 mmol) inethanol (50 mL) was added thiourea (760 mg, 9.98 mmol). The resultingsolution was stirred for 1 h at 100° C. and then cooled down roomtemperature. The mixture was filtered to afford1-(2-amino-5-methyl-1,3-thiazol-4-yl)ethan-1-one as a off-white solid(1.2 g, 65%). LCMS (ESI): [M+H]⁺=157.0.

Step 3:3-acetyl-7-(chloromethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a solution of 1-(2-amino-5-methyl-1,3-thiazol-4-yl)ethan-1-one (300mg, 1.92 mmol) was added ethyl 4-chloro-3-oxobutanoate (474 mg, 2.88mmol) and polyphosphoric acid (10 mL). The resulting solution wasstirred for 1 h at 110° C. and then cooled down room temperature. Theresulting solution was diluted with water (20 mL) and the pH value ofthe solution was adjusted to 8. The resulting solution was extracted andconcentrated in vacuo. The residue was purified by chromatography withethyl acetate/petroleum (1/1) to afford3-acetyl-7-(chloromethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas a light yellow solid (70.0 mg, 12%). LCMS (ESI): [M+H]⁺=257.0; ¹H NMR(300 MHz, CDCl₃) δ 6.46 (s, 1H), 4.42 (s, 2H), 2.52 (s, 3H), 2.39 (s,3H).

Step 4:3-acetyl-2-methyl-7-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-acetyl-7-(chloromethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(200 mg, 0.78 mmol) in CH₃CN (25 mL) was added potassium iodide (68 mg,0.39 mmol), potassium carbonate (220 mg, 1.59 mmol) and3-(trifluoromethyl)-1H-pyrazole (160 mg, 1.18 mmol). The resultingsolution was stirred for 12 h at 80° C. in an oil bath. The resultingmixture was quenched by water (10 mL), extracted with dichloromethane(3×20 mL), washed with brine, dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by chromatographywith ethyl acetate/petroleum ether (1:2) to afford3-acetyl-2-methyl-7-[[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(195 mg, 70%) as a yellow solid. LCMS (ESI): [M+H]⁺=357.1; ¹H NMR (300MHz, CDCl₃) δ 7.61 (m, 1H), 6.62 (m, 1H), 5.91 (s, 1H), 5.25 (s, 2H),2.45 (s, 3H), 2.38 (s, 3H).

Step 5:3-(1-hydroxyethyl)-2-methyl-7-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-acetyl-2-methyl-7-[[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(30 mg, 0.08 mmol) in methanol (10 mL) was added sodium boronhydride (13mg, 0.34 mmol). The resulting solution was stirred for 12 h at roomtemperature in an oil bath. The reaction was then quenched by aqueousammonium chloride (10 ml), extracted with dichloromethane (3×20 mL),washed with brine, dried over anhydrous magnesium sulfate andconcentrated under vacuum. The residue was purified by chromatographywith ethyl acetate/petroleum ether (1:1) to afford3-(1-hydroxyethyl)-2-methyl-7-[[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(11.7 mg, 39%) as a light yellow solid. LCMS (ESI): [M+H]⁺=359.0; ¹H NMR(300 MHz, CD₃OD) δ 7.94-7.93 (m, 1H), 6.70 (m, 1H), 5.97 (s, 1H),5.47-5.40 (m, 1H), 5.38 (m, 2H), 2.48 (s, 3H), 1.52 (m, 3H).

The following examples were prepared in a manner similar to Example18.1:

LCMS No. Structure/Name (M + H) ¹H NMR 18.2

397.0 ¹H NMR (300 MHz, CD₃OD) δ 6.33 (s, 1H), 5.83 (s, 1H), 5.44 (s,2H), 2.41 (s, 3H), 2.37 (s, 3H), 1.92 (m, 1H), 1.02 (m, 2H), 0.76 (m,2H) 3-acetyl-7-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 18.3

397.0 ¹H NMR (300 MHz, CD₃OD) δ 6.58 (s, 1H), 5.69 (s, 1H), 5.32 (s,2H), 2.41 (s, 3H), 2.37 (s, 3H), 1.98 (m, 1H), 0.98 (m, 2H), 0.78 (m,2H) 3-acetyl-7-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

The following compounds were prepared using methods analogous to thosedescribed above:

LCMS No. Structure/Name (M + H) ¹H NMR 18.4

373.10 ¹H NMR (300 MHz, CDCl₃) δ 7.60 (m, 1H), 7.15 (m, 1H), 6.61 (m,1H), 5.98 (s, 1H), 5.26 (s, 2H), 2.52 (s, 3H), 1.72 (s, 6H)3-(2-hydroxypropan-2-yl)-2-methyl-7-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-5H-thiazolo[3,2-a]pyrimidin-5-one 18.5

373 ¹H NMR (300 MHz, CDCl₃): δ 7.35-7.25 (m, 2H), 7.19- 7.12 (m, 1H),5.72 (s, 1H), 5.42 (s, 2H), 5.04 (m, 1H), 2.56 (s, 3H), 2.41 (s, 3H),1.60 (m, 3H) 7-((5-fluoro-3-methyl-1H-indazol-1-yl)methyl)-3-(1-hydroxyethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

Method 19 Example 19.1:7-(1-(5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

Step 1:3-(trans-2-((tert-butyldimethylsilyloxy)methyl)cyclopropyl)-7-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of7-[[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(from Example 15.11) (120 mg, 0.28 mmol) in dichloromethane (30 mL) wasadded tert-butyldimethylsilylchloride (177 mg, 1.18 mmol), imidazole (80mg, 1.18 mmol) and 4-dimethylaminopyridine (5 mg, cat.). The resultingsolution was stirred for overnight at 50° C. After cooling down to roomtemperature, the reaction mixture was concentrated under vacuum. Theresidue was purified by silica gel chromatography with ethylacetate/petroleum ether (1:2) to afford3-(2-[[(tert-butyldimethylsilyl)oxy]methyl]cyclopropyl)-7-[[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(120 mg, 67%) as yellow oil. LCMS (ESI): [M+H]⁺=539.0. The crude productwas used in next step without further purification.

Step 2:3-(trans-2-((tert-butyldimethylsilyloxy)methyl)cyclopropyl)-7-(1-(5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-(2-[[(tert-butyldimethylsilyl)oxy]methyl]cyclopropyl)-7-[[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(120 mg, 0.22 mmol) in tetrahydrofuran (20 mL) was added n-butyllithium(1.5 mL, 85% in hexanes) and methyl iodide (158 mg, 1.11 mmol). Theresulting solution was stirred overnight at room temperature. Thereaction was then quenched with water (20 mL), extracted withdichloromethane (3×30 mL), washed with brine, dried over sodium sulfateand concentrated under vacuum. The residue was then purified bychromatography with ethyl acetate/petroleum ether (1:2) to afford3-(trans-2-[[(tert-butyldimethylsilyl)oxy]methyl]cyclopropyl)-7-[1-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(50 mg, 35%) as a light yellow solid. LCMS (ESI): [M+H]⁺=553.0.

Step 3:7-(1-(5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-(trans-2-[[(tert-butyldimethylsilyl)oxy]methyl]cyclopropyl)-7-[1-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(50 mg, 0.09 mmol) in ethanol (30 mL) was added 0.5% hydrogen chloridein ethanol (10 mL). The resulting solution was stirred for 2 h at roomtemperature. After cooling down to room temperature, the reactionmixture was concentrated under vacuum. The residue was purified bychromatography with dichloromethane/methanol (100:1) to afford7-[1-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(14.3 mg, 34%) as a white solid. LCMS (ESI): [M+H]⁺=439.0; ¹H NMR (300MHz, CD₃OD) δ 6.18 (s, 2H), 6.17 (s, 1H), 5.59-5.54 (m, 1H), 4.05-4.01(m, 1H), 3.14-3.07 (m, 1H), 2.41 (s, 3H), 2.28-2.22 (m, 1H), 1.96-1.93(m, 3H), 1.69-1.64 (m, 1H), 1.27-1.23 (m, 1H), 1.03-0.72 (m, 4H),0.73-0.62 (m, 2H).

The following compound was prepared using methods analogous to thosedescribed above:

LCMS No. Structure/Name (M + H) ¹H NMR 19.2

439.0 ¹H NMR (300 MHz, CD₃OD) δ 6.18 (s, 1H), 5.73-5.70 (m, 1H),5.60-5.57 (m, 1H), 4.03-3.96 (m, 1H), 3.42-3.35 (m, 1H), 2.41 (s, 3H),1.98-1.92 (m, 4H), 1.71-1.63 (m, 1H), 2.52 (s, 3H), 1.45-1.40 (m, 1H),1.06-0.92 (m, 3H), 0.73- 0.65 (m, 3H)7-(1-(5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)-3-(2-(hydroxymethyl)-1-methylcyclopropyl)-2-methyl-5H- thiazolo[3,2-a]pyrimidin-5-one

Method 20 Example 20.1:3-((3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile

Step 1:3-((3-bromo-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile

To a solution of3-bromo-7-(chloromethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(from Example 4.1, Step 6) (500 mg, 1.70 mmol) in 1,4-dioxane/H₂O (3/1mL) was added tetrakis(triphenylphosphine)palladium (198 mg, 0.17 mmol),potassium phosphate (726 mg, 3.42 mmol) and (3-cyanophenyl)boronic acid(302 mg, 2.06 mmol). The resulting solution was stirred overnight at 80°C. After cooling down to room temperature, the resulting mixture wasextracted with dichloromethane (3×30 mL), washed with brine (1×30 mL),dried over anhydrous sodium sulfate and concentrated in vacuo. Theresidue was purified by silica gel chromatography with ethylacetate/petroleum ether (1:2) to afford3-([3-bromo-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-7-yl]methyl)benzonitrile(102 mg, 17%) as a brown solid. LCMS (ESI): [M+H]⁺=360.0, 362.0; ¹H NMR(300 MHz, CDCl₃) δ 7.65-7.41 (m, 4H), 6.04 (s, 1H), 3.91 (s, 2H), 2.35(s, 3H).

Step 2:3-((3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile

To a solution of3-((3-bromo-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile(80 mg, 0.22 mmol) in CH₃CN/H₂O (3/1 ml) was added[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (16.7 mg,0.02 mmol), sodium carbonate (47.2 mg, 0.45 mmol) and potassiumtrans-2-(hydroxymethyl)cyclopropyltrifluoroborate (from Example 4.1,Step 2) (79.3 mg, 0.45 mmol). The reaction mixture was irradiated in amicrowave for 1.5 h at 120° C. The resulting mixture was extracted withdichloromethane (3×20 mL), washed with brine (10 mL), dried over sodiumsulfate. After concentration under vacuum, the residue was purified on asilica gel column eluted with dichloromethane/methanol (50:1) to afford3-([3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-7-yl]methyl)benzonitrile(16.6 mg, 21%) as a white solid. LCMS (ESI): [M+H]⁺=352.0; ¹H NMR (300MHz, CDCl₃) δ 7.62-7.58 (m, 3H), 7.50-7.44 (m, 1H), 6.02 (s, 1H),4.04-4.00 (m, 1H), 3.99 (s, 2H), 3.20-3.13 (m, 1H), 2.42 (s, 3H),2.26-2.25 (m, 1H), 1.28-1.25 (m, 1H), 1.05-1.00 (m, 2H).

Example 20.2:3-((6-fluoro-3-(2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile

Step 1:3-((3-bromo-6-fluoro-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile

To a solution of3-bromo-7-(chloromethyl)-6-fluoro-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(from Example 4.29, Step 1) (130 mg, 0.42 mmol) in 1,4-dioxane/H₂O (3/1,4 mL) added tetrakis(triphenylphosphine)palladium (48 mg, 0.04 mmol),potassium phosphate (179 mg, 0.84 mmol), and (3-cyanophenyl)boronic acid(74 mg, 0.50 mmol). The resulting solution was stirred overnight at 80°C., then the resulting mixture was concentrated under vacuum and theresidue was purified by chromatography with ethyl acetate/petroleumether (1:3) to afford3-([3-bromo-6-fluoro-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-7-yl]methyl)benzonitrile(36 mg, 23%) as a light yellow solid. LCMS (ESI): [M+H]⁺=377.9.

Step 2:3-((6-fluoro-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile

To a solution of3-([3-bromo-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-7-yl]methyl)-2-fluorobenzonitrile(100 mg, 0.26 mmol) in CH₃CN/H₂O (3/1 mL) under inert nitrogenatmosphere was added [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride (20 mg, 0.03 mmol), sodium carbonate (56.2 mg, 0.53 mmol),and potassium trans-2-(hydroxymethyl)cyclopropyltrifluoroborate (fromExample 4.1, Step 2) (94.4 mg, 0.53 mmol). The resulting solution wasstirred for 90 min at 120° C. The mixture was concentrated under vacuum,and the residue was purified by chromatography withdichloromethane/methanol (50:1) to afford2-fluoro-3-([3-[trans2-(hydroxymethyl)cyclopropyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-7-yl]methyl)benzonitrileas a off-white solid (9.9 mg, 10%). LCMS (ESI): [M+H]⁺=370.0; ¹H NMR(300 MHz, CDCl₃) δ 7.57 (s, 1H), 7.55-7.52 (m, 2H), 7.41-7.40 (m, 1H),4.06-3.96 (m, 3H), 3.22-3.17 (m, 1H), 2.37 (s, 3H), 2.30-2.10 (m, 1H),1.34-1.25 (m, 1H), 1.06-0.98 (m, 2H).

The following examples were prepared in a manner similar to Example 20.1and 20.2:

LCMS No. Structure/Name (M + H) ¹H NMR 20.3

370.0 ¹H NMR (300 MHz, CDCl₃) δ 7.64-7.57 (m, 2H), 7.29-7.24 (m, 1H),6.07 (s, 1H), 4.09-4.04 (m, 1H), 3.99 (s, 2H), 3.18-3.11 (m, 1H), 2.41(s, 3H), 2.32-2.26 (m, 1H), 1.29-1.24 (m, 1H), 1.06-0.99 (m, 2H)2-fluoro-3-((3-(trans-2- (hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7- yl)methyl)benzonitrile 20.4

378.1 ¹H NMR (300 MHz, CDCl₃) δ 9.28 (br, 1H), 8.48 (br, 1H), 8.11- 8.09(m, 1H), 8.02-7.99 (m, 1H), 7.86-7.81 (m, 1H), 7.75-7.70 (m, 1H), 5.99(s, 1H), 4.36 (s, 2H), 4.08-4.00 (m, 2H), 3.09-3.02 (m, 1H), 2.36 (s,3H), 2.26-2.21 (m, 1H), 1.28-1.20 (m, 1H), 1.03-0.97 (m, 2H)3-(trans-2-(hydroxymethyl)cyclopropyl)-7-(isoquinolin-4-ylmethyl)-2-methyl-5H- thiazolo[3,2-a]pyrimidin-5-one20.5

395.0 ¹H NMR (300 MHz, CDCl₃) δ 7.53-7.41 (m, 4H), 6.02 (s, 1H),4.14-4.02 (m, 1H), 3.92 (s, 2H), 3.13-3.05 (m, 1H), 2.39 (s, 3H),2.37-2.26 (m, 1H), 1.30-1.20 (m, 1H), 1.04-0.95 (m, 2H)3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-7-(3-(trifluoromethyl)benzyl)-5H- thiazolo[3,2-a]pyrimidin-5-one

The following compounds were prepared using methods analogous to thosedescribed above:

LCMS No. Structure/Name (M + H) ¹H NMR 20.6 

366.00 ¹H NMR (300 MHz, CD₃OD) δ 7.54 (m, 2H), 7.36 (m, 1H), 5.94 (s,1H), 3.97 (s, 2H), 3.59 (m, 2H), 2.42 (s, 3H), 2.41 (s, 3H), 2.15 (m,1H), 1.32 (m, 1H), 1.01 (m, 2H) 3-((3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7- yl)methyl)-4-methylbenzonitrile 20.7 

379.95 ¹H NMR (300 MHz, CDCl₃) δ 7.62-7.57 (m, 2H), 7.19-7.15 (m, 1H),6.05 (s, 1H), 4.17-4.05 (m, 2H), 3.90 (s, 2H), 3.12-3.07 (m, 1H), 2.38(s, 3H), 2.28-2.26 (m, 1H), 1.30-1.24 (m, 1H), 1.04-0.98 (m, 2H)4-fluoro-3-((3-(trans-2- (hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7- yl)methyl)benzonitrile 20.8 

370.10 ¹H NMR (300 MHz, CDCl₃) δ 7.42 (s, 1H), 7.30-7.28 (m, 2H), 6.10(s, 1H), 4.10-4.05 (m, 1H), 3.91 (s, 2H), 3.18-3.11 (m, 1H), 2.41 (s,3H), 2.35-2.25 (m, 1H), 1.35-1.25 (m, 1H), 1.07-1.00 (m, 2H)3-fluoro-5-((3-(trans-2- (hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7- yl)methyl)benzonitrile 20.9 

370.0  ¹H NMR (300 MHz, CDCl₃) δ 7.59-7.48 (m, 2H), 7.20-7.14 (m, 1H),6.06 (s, 1H), 4.14-4.03 (m, 1H), 3.85 (s, 2H), 3.10 (m, 1H), 2.39 (s,3H), 2.31-2.24 (m, 1H), 1.26-1.23 (m, 1H), 1.06-1.01 (m, 2H)2-fluoro-5-((3-(trans-2- (hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7- yl)methyl)benzonitrile 20.10

382.0  ¹H NMR (400 MHz, CDCl₃) δ 7.60-7.58 (m, 1H), 7.50 (s, 1H),6.94-6.92 (m, 1H), 5.96 (s, 1H), 4.06-4.03 (m, 1H), 3.89-3.85 (m, 5H),3.13-3.07 (m, 1H), 2.38 (s, 3H), 2.29-2.26 (m, 1H), 1.28-1.25 (m, 2H),1.05-0.88 (m, 2H) 3-[[3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl]methyl]- 4-methoxy-benzonitrile 20.11

395.0  ¹H NMR (300 MHz, CDCl₃) δ 7.60-7.59 (m, 2H), 7.40-7.37 (m, 2H),6.04 (s, 1H), 4.21-4.18 (m, 1H), 4.07-4.01 (m, 1H), 3.91 (s, 2H),3.11-3.04 (m, 1H), 2.39 (s, 3H), 2.36-2.24 (m, 1H), 1.25-1.19 (m, 1H),1.04-0.99 (m, 2H) 3-(2-(hydroxymethyl)cyclopropyl)-2-methyl-7-(4-(trifluoromethyl)benzyl)-5H- thiazolo[3,2-a]pyrimidin-5-one20.12

352.9  ¹H NMR (300 MHz, CDCl₃) δ 8.62-8.61 (m, 1H), 7.86 (m, 1H),7.64-7.62 (m, 1H), 6.21 (s, 1H), 3.99 (s, 2H), 3.63-3.57 (m, 2H), 2.41(s, 3H), 2.20-2.11 (m, 1H), 1.40-1.28 (m, 1H), 1.05-0.99 (m, 2H)4-((3-(trans-2- (hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7- yl)methyl)picolinonitrile 20.13

392.0  ¹H NMR (300 MHz, CDCl₃) δ 7.47-7.45 (m, 1H), 7.40-7.22 (m, 2H),5.90 (s, 1H), 4.19 (s, 2H), 4.06-3.98 (m, 1H), 3.14-3.07 (m, 1H), 2.45(s, 3H), 2.31-2.26 (m, 1H), 1.95-1.86 (m, 1H), 1.30-1.26 (m, 1H),1.04-0.99 (m, 4H), 0.69- 0.68 (m, 2H) 4-cyclopropyl-3-((3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7- yl)methyl)benzonitrile

Method 21 Example 21.1:7-(3-cyanobenzyl)-N,2-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

Step 1:7-(3-cyanobenzyl)-N,2-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

7-(Chloromethyl)-N,2-dimethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(from Example 16.1, Step 5) (50 mg, 0.18 mmol), (3-cyanophenyl)boronicacid (56 mg, 0.38 mmol), tetrakis(triphenylphosphine)palladium (20 mg,0.019 mmol), potassium phosphate (80 mg, 0.38 mmol), 1,4-dioxane (1.5mL) and water (0.5 mL) were placed in a 10-mL sealed tube. The resultingsolution was stirred for 2 h at 80° C. in an oil bath. After coolingdown to room temperature, the resulting mixture was extracted withCH₂Cl₂ (20 mL), washed with brine, dried over anhydrous sodium sulfateand concentrated in vacuo. The residue was purified by chromatographywith dichloromethane/methanol (20:1) to afford7-[(3-cyanophenyl)methyl]-N,2-dimethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(29.1 mg, 47%) as a white solid. LCMS (ESI): [M+H]⁺=339.0; ¹H NMR (300MHz, CDCl₃) δ 7.61-7.40 (m, 4H), 6.08 (s, 1H), 5.96 (br, 1H), 3.90 (s,2H), 3.05 (m, 3H), 2.41 (s, 3H).

The following examples were prepared in a manner similar to Example21.1:

LCMS No. Structure/Name (M + H) ¹H NMR 21.2 

356.9 ¹H NMR (300 MHz, DMSO) δ 8.32 (m, 1H), 7.84 (m, 2H), 7.38 (m, 1H),6.13 (s, 1H), 4.00 (s, 2H), 2.72 (s, 3H), 2.28 (s, 3H)7-(3-cyano-2-fluorobenzyl)-N,2-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3- carboxamide 21.3 

380.10 ¹H NMR (300 MHz, CDCl₃) δ 7.34-7.29 (m, 1H), 7.17-7.12 (m, 1H),7.07-7.02 (m, 1H), 6.04 (s, 1H), 5.88 (br, 1H), 3.94 (s, 2H), 3.56-3.47(m, 2H), 2.40 (s, 3H), 1.30-1.25 (m, 3H)7-(3-chloro-2-fluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3- carboxamide 21.4 

400.0 ¹H NMR (300 MHz, CD₃OD) δ 7.63 (m, 2H), 7.32 (m, 1H), 6.14 (s,1H), 4.05 (s, 2H), 3.92 (s, 3H), 2.38 (s, 3H)N-ethyl-7-(2-fluoro-3-(trifluoromethyl)benzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine- 3-carboxamide 21.5 

360.0 ¹H NMR (300 MHz, CDCl₃) δ 7.30-7.26 (m, 1H), 7.12-6.96 (m, 3H),6.03 (s, 1H), 6.00 (s, 1H), 3.91 (s, 2H), 3.55-3.46 (m, 2H), 2.37 (s,3H), 2.26 (s, 3H), 1.29-1.24 (m, 3H)N-ethyl-7-(2-fluoro-3-methylbenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3- carboxamide 21.6 

386.7 ¹H NMR (300 MHz, CDCl₃) δ 7.59 (s, 1H), 7.50 (s, 2H), 6.05 (s,1H), 5.82 (m, 1H), 4.27 (s, 2H), 3.55- 3.51 (m, 3H), 2.44 (s, 3H),1.30-1.26 (m, 3H) 7-(2-chloro-5-cyanobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3- carboxamide 21.7 

396.0 ¹H NMR (300 MHz, CDCl₃) δ 7.43-7.61 (m, 4H), 6.06 (s, 1H), 5.81(br, 1H), 3.93 (s, 2H), 3.48-3.57 (m, 2H), 2.42 (s, 3H), 1.28 (m, 3H)N-ethyl-2-methyl-5-oxo-7-(3- (trifluoromethyl)benzyl)-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.8 

353.0 ¹H NMR (300 MHz, CDCl₃) δ 7.56-7.40 (m, 4H), 6.08 (s, 1H), 5.83(s, 1H), 3.90 (s, 2H), 3.53 (m, 2H), 2.42 (s, 3H), 1.28 (m, 3H)7-(3-cyanobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.9 

397.0 ¹H NMR (300 MHz, CDCl₃) δ 7.56-7.49 (m, 2H), 6.06 (s, 1H), 5.85(s, 1H), 3.93 (s, 2H), 3.58- 3.45 (m, 2H), 2.18-2.09 (m, 1H), 1.18-1.15(m, 3H), 1.13-1.11 (m, 2H), 0.85- 0.79 (m, 2H)7-(3-cyano-2-fluorobenzyl)-2-cyclopropyl-N-ethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3- carboxamide 21.10

371.0 ¹H NMR (300 MHz, CDCl₃) δ 7.37 (s, 1H), 7.23-7.22 (m, 2H), 6.10(s, 1H), 5.82-5.73 (m, 1H), 3.89 (s, 2H), 3.58-3.50 (m, 2H), 2.43 (s,3H), 1.31-1.26 (m, 3H) 7-(3-cyano-5-fluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3- carboxamide 21.11

339.0 ¹H NMR (300 MHz, CD₃OD) δ 7.36-7.29 (m, 1H), 7.13-6.94 (m, 3H),6.15 (s, 1H), 3.93 (s, 2H), 3.41 (m, 2H), 2.40 (s, 3H), 1.24 (m, 3H)7-(3-cyanobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.12

414.0 ¹H NMR (300 MHz, CDCl₃) δ 7.53 (m, 2H), 7.23 (m, 1H), 6.05 (s,1H), 5.88 (s, 1H), 3.96 (s, 2H), 3.52 (m, 2H), 2.40 (s, 3H), 1.27 (m,3H) N-ethyl-7-(2-fluoro-3-(trifluoromethyl)benzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine- 3-carboxamide 21.13

371.0 ¹H NMR (300 MHz, CDCl₃) δ 7.61-7.50 (m, 2H), 7.26-7.20 (m, 1H),6.07 (s, 1H), 5.85 (s, 1H), 3.95 (s, 2H), 3.57-3.48 (m, 2H), 2.42 (s,3H), 1.28 (m, 3H) 7-(3-cyano-2-fluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3- carboxamide 21.14

366.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.30 (q, J = 4.6 Hz, 1H), 7.53-7.45(m, 1H), 7.39-7.31 (m, 1H), 7.24-7.16 (m, 1H), 6.08 (s, 1H), 2.73 (dd, J= 4.7, 0.9 Hz, 3H), 2.29 (d, J = 0.9 Hz, 3H).7-[(3-chloro-2-fluoro-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide 21.15

382.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.29 (d, J = 4.8 Hz, 1H), 7.68 (s,1H), 7.65-7.52 (m, 3H), 6.19 (s, 1H), 3.98 (s, 2H), 2.73 (d, J = 4.6 Hz,3H), 2.29 (s, 3H). N,2-dimethyl-5-oxo-7-[[3-(trifluoromethyl)phenyl]methyl]thiazolo[3,2- a]pyrimidine-3-carboxamide21.16

348.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.29 (q, J = 4.6 Hz, 1H), 7.37 (t, J =1.9 Hz, 1H), 7.34 (d, J = 7.4 Hz, 1H), 7.28 (ddt, J = 11.5, 7.4, 1.6 Hz,2H), 6.16 (s, 1H), 3.88 (s, 2H), 2.73 (d, J = 4.7 Hz, 3H), 2.29 (s, 3H).7-[(3-chlorophenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.17

422.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.37-8.29 (m, 1H), 7.59 (d, J = 2.0Hz, 1H), 7.56-7.49 (m, 1H), 7.17 (d, J = 8.1 Hz, 1H), 5.99 (d, J = 0.7Hz, 1H), 4.18 (s, 2H), 2.73 (d, J = 4.7 Hz, 3H), 2.29 (s, 3H), 2.11-2.03(m, 1H), 1.02- 0.90 (m, 2H), 0.76-0.64 (m, 2H). 7-[[2-cyclopropyl-5-(trifluoromethyl)phenyl]methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide

Example 21.18:N-ethyl-2-methyl-5-oxo-7-((6-(trifluoromethyl)pyridine-2-yl)methyl)-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

Step 1: Bis(pinacolato)diboron

To a solution of 2-bromo-6-(trifluoromethyl)pyridine (500 mg, 2.21 mmol)in 1,4-dioxane (10 mL) under nitrogen, was added potassium acetate (862mg, 8.78 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride (330 mg, 0.45 mmol),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(609 mg, 2.40 mmol). The resulting solution was stirred for 12 h at 90°C. The mixture was filtered to remove solids and concentrated undervacuum to afford [6-(trifluoromethyl) yridine-2-yl]boronic acid (500 mg,crude) as a black solid. The crude product was used in the next stepwithout further purification. LCMS (ESI): [M+H]⁻=191.9.

Step 2:N-ethyl-2-methyl-5-oxo-7-((6-(trifluoromethyl)pyridine-2-yl)methyl)-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

To a solution of7-(chloromethyl)-N-ethyl-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(prepared in a similar manner to Example 16.1, Step 5) (50 mg, 0.17mmol) in 1,4-dioxane (2 mL) under nitrogen was added sodium carbonate(36 mg, 0.34 mmol), [6-(trifluoromethyl)pyridine-2-yl]boronic acid (50mg, 0.26 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride (13 mg, 0.02 mmol, and water (0.2 mL). The reaction mixturewas irradiated with microwave radiation for 20 min at 120° C. Theresulting solution was then extracted with ethyl acetate (3×20 mL),washed with brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was purified by chromatography withdichloromethane/methanol (20:1) to affordN-ethyl-2-methyl-5-oxo-7-[[6-(trifluoromethyl)pyridine-2-yl]methyl]-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(22.8 mg, 33%) as a yellow solid. LCMS (ESI): [M+H]⁺=397.1; ¹H NMR (400MHz, CDCl₃) δ 7.81 (m, 1H), 7.60 (m, 1H), 7.53 (m, 1H), 6.26 (s, 1H),5.89 (s, 1H), 4.15 (s, 2H), 3.51 (m, 2H), 2.41 (s, 3H), 1.28 (m, 3H).

Example 21.19:N-ethyl-7-(2-ethyl-4,5-difluorobenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

Step 1: 1-(benzyloxy)-2-bromo-4,5-difluorobenzene

To a mixture of 2-bromo-4,5-difluorophenol (500 mg, 2.39 mmol, 1.00equiv) and potassium carbonate (800 mg, 5.80 mmol) in CH₃CN (10 mL) wasadded (bromomethyl)benzene (610 mg, 3.57 mmol). The resulting solutionwas stirred for 3 h at 80° C. in an oil bath. After filtration to removesolids and concentration, the residue was purified by chromatographywith ethyl acetate/petroleum ether (1:30) to afford1-(benzyloxy)-2-bromo-4,5-difluorobenzene (600 mg, 84%) as colorlessoil. ¹H NMR (300 MHz, CDCl₃) δ 7.46-7.32 (m, 5H), 6.82-6.76 (m, 1H),5.10 (s, 2H).

Step 2: 1-(benzyloxy)-4,5-difluoro-2-vinylbenzene

1-(Benzyloxy)-2-bromo-4,5-difluorobenzene (560 mg, 1.87 mmol),tetrakis(triphenylphosphine)palladium (200 mg, 0.19 mmol), potassiumphosphate (800 mg, 3.78 mmol), 1,4-dioxane (10 mL), water (1 mL) and2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (580 mg, 3.77 mmol)were placed in a 30-mL sealed tube. The reaction mixture was stirred for5 h at 80° C. in an oil bath. After filtration to remove solids andconcentration, the residue was purified by chromatography with ethylacetate/petroleum ether (1:10) to afford1-(benzyloxy)-2-ethenyl-4,5-difluorobenzene (350 mg, 76%) as lightyellow oil. ¹H NMR (300 MHz, CDCl₃) δ 7.69-7.29 (m, 6H), 7.07-6.95 (m,1H), 6.81-6.71 (m, 1H), 5.69-5.63 (m, 1H), 5.29-5.25 (m, 1H), 5.04 (s,2H).

Step 3: 2-ethyl-4,5-difluorophenol

To a mixture of 1-(benzyloxy)-2-ethenyl-4,5-difluorobenzene (350 mg,1.42 mmol) in methanol (10 mL) was added palladium on carbon (20 mg).The resulting reaction was stirred overnight at room temperature underhydrogen atmosphere (1 atm). After filtration to remove catalyst, thefiltrate was concentrated under vacuum to afford2-ethyl-4,5-difluorophenol (200 mg, 89%) as light yellow oil. The crudeproduct was used in the next step without further purification.

Step 4: 2-ethyl-4,5-difluorophenyl trifluoromethanesulfonate

To a mixture of 2-ethyl-4,5-difluorophenol (200 mg, 1.26 mmol) andtriethylamine (260 mg, 2.58 mmol) in dichloromethane (10 mL) was addedtrifluoroacetic anhydride (680 mg, 2.42 mmol) dropwise with stirring at0° C. The resulting solution was stirred for 30 min at 0° C. Thereaction was then quenched by the addition of water, extracted withdichloromethane (10 mL×2), washed with brine, dried over anhydroussodium sulfate and concentrated in vacuo to afford2-ethyl-4,5-difluorophenyl trifluoromethanesulfonate (180 mg, 50%) as alight yellow oil. The crude product was used in next step withoutfurther purification.

Step 5:2-(2-ethyl-4,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a mixture of 2-ethyl-4,5-difluorophenyl trifluoromethanesulfonate(180 mg, 0.62 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride (50 mg, 0.07 mmol), potassium acetate (120 mg, 1.23 mmol) in1,4-dioxane (5 mL) was added4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(240 mg, 0.93 mmol). The resulting mixture was stirred overnight at 90°C. in an oil bath under nitrogen atmosphere. After filtration to removesolids and concentration, the residue was purified by chromatographywith ethyl acetate/petroleum ether (1:10) to afford2-(2-ethyl-4,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(140 mg, 84%) as a light yellow oil. The crude product was used in nextstep without further purification.

Step 6:N-ethyl-7-(2-ethyl-4,5-difluorobenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

7-(Chloromethyl)-N-ethyl-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(prepared in a manner similar to Example 16.1, Step 5) (100 mg, 0.35mmol, 1.00 equiv),2-(2-ethyl-4,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(140 mg, 0.52 mmol, 1.50 equiv),[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (30 mg,0.10 equiv), sodium carbonate (75 mg, 2.00 equiv), 1,4-dioxane (3 mL)and water (0.3 mL) were placed in a 10 mL sealed tube. The reactionmixture was irradiated with microwave radiation for 30 min at 120° C.The resulting solution was diluted with 30 mL of dichloromethane, washedwith 2×10 mL of brine, dried over sodium sulfate and concentrated invacuo. The residue was purified by silica gel chromatography withdichloromethane/methanol (40:1) to affordN-ethyl-7-[(2-ethyl-4,5-difluorophenyl)methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(17.9 mg, 13%) as an off-white solid. LCMS (ESI): [M+H]⁺=392.0; ¹H NMR(300 MHz, CDCl₃) δ 7.04-6.91 (m, 2H), 5.88 (s, 1H), 5.82 (br, 1H), 3.84(s, 2H), 3.58-3.48 (m, 2H), 2.59-2.52 (m, 2H), 2.42 (s, 3H), 1.28 (m,3H), 1.17 (m, 3H).

Example 21.20:7-[[3-(difluoromethyl)-2-fluoro-phenyl]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide

Step 1: 3-bromo-2-fluorobenzaldehyde

To a solution of (3-bromo-2-fluoro-phenyl)methanol (2.750 g, 13.413mmol) in dichloromethane (50 mL) was added manganese dioxide (9.32 g,107.31 mmol) and the resulting mixture was stirred at 45° C. overnight.Once complete, the reaction was filtered through diatomaceous earth andwashed with dichloromethane to obtain 3-bromo-2-fluoro-benzaldehyde as awhite solid (2.24 g, 83%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.19 (dt, J=1.3,0.7 Hz, 1H), 8.05 (tdd, J=6.8, 3.1, 1.5 Hz, 1H), 7.85 (ddt, J=7.9, 6.4,1.5 Hz, 1H), 7.37 (tdt, J=7.8, 1.6, 0.8 Hz, 1H).

Step 2: 1-bromo-3-(difluoromethyl)-2-fluorobenzene

To a solution of 3-bromo-2-fluorobenzaldehyde (1980 mg, 9.5581 mmol) indichloromethane (30 mL, 468.0 mmol) under inert atmosphere was addeddiethylaminosulfur trifluoride (2.53 mL, 19.116 mmol) at 0° C., and themixture was stirred for 1 h at 0° C. The mixture was warmed to roomtemperature and stirred for 1 h. The reaction was carefully quenchedwith saturated sodium bicarbonate solution. The reaction mixture wasthen diluted with ethyl acetate (300 mL) and the organic layer waswashed with saturated sodium bicarbonate solution and brine thenconcentrated to dryness and purified by chromatography (0-50% ethylacetate in heptane over 20 minutes) to provide1-bromo-3-(difluoromethyl)-2-fluorobenzene (1.35 g, 61%). ¹H NMR (400MHz, DMSO-d₆) δ 7.93 (ddq, J=7.9, 6.8, 1.2 Hz, 1H), 7.66 (ddq, J=7.6,6.4, 1.2 Hz, 1H), 7.33 (td, J=7.9, 1.0 Hz, 1H), 7.24 (t, J=54.1 Hz, 1H).

Step 3:2-[3-(difluoromethyl)-2-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A mixture of 1-bromo-3-(difluoromethyl)-2-fluorobenzene (1.18 g, 5.09mmol) and bis(pinacolato)diboron (2.59 g, 10.2 mmol)1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (280 mg, 0.382mmol) and potassium acetate (1.50 g, 15.3 mmol) in 1,4-dioxane (15 mL)was heated at 100° C. overnight. The reaction mixture was filteredthrough diatomaceous earth and concentrated. The crude material waspurified by chromatography (0-50% ethyl acetate in heptane) to obtain2-[3-(difluoromethyl)-2-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneas a light yellow solid (1.11 g, 80%). ¹H NMR (400 MHz, DMSO-d₆) δ7.86-7.73 (m, 2H), 7.36 (t, J=7.5 Hz, 1H), 7.18 (t, J=54.4 Hz, 1H), 1.31(s, 12H).

Step 4:7-[[3-(difluoromethyl)-2-fluoro-phenyl]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide

A mixture of7-(chloromethyl)-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide(prepared in a similar manner as Example 16.1, Step 5) (75 mg, 0.262mmol),2-[3-(difluoromethyl)-2-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(214 mg, 0.787 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladiumdichloride (14.4 mg, 0.0197 mmol) and potassium carbonate (110 mg, 0.787mmol) in acetonitrile (3 mL) and water (0.75 mL) was heated at 120° C.in the microwave for 40 minutes. The reaction mixture was filteredthrough diatomaceous earth and concentrated. The crude material waspurified by chromatography (0-100% ethyl acetate in heptane) to obtain7-[[3-(difluoromethyl)-2-fluoro-phenyl]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide(49.6 mg, 47%). LCMS (ESI): [M+H]⁺=396.1; ¹H NMR (400 MHz, DMSO-d₆) δ8.37 (t, J=5.7 Hz, 1H), 7.55 (q, J=8.0 Hz, 2H), 7.38-7.02 (m, 2H), 6.08(s, 1H), 3.97 (s, 2H), 3.27-3.16 (m, 2H), 2.29 (s, 3H), 1.09 (t, J=7.2Hz, 3H).

The following examples were prepared in a manner similar to Example21.18, 21.19, and 21.20:

LCMS No. Structure/Name (M + H) ¹H NMR 21.21

374.0 ¹H NMR (300 MHz, CDCl₃) δ 7.24-7.14 (m, 1H), 6.95-6.84 (m, 2H),5.87 (s, 1H), 5.84 (s, 1H), 3.91 (s, 2H), 3.56-3.47 (m, 2H), 2.60-2.53(m, 2H), 2.41 (s, 3H), 1.29-1.23 (m, 3H), 1.19- 1.14 (m, 3H)N-ethyl-7-(2-ethyl-4,5-difluorobenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine- 3-carboxamide 21.22

354.05 ¹H NMR (300 MHz, CDCl₃) δ 7.61-7.50 (m, 2H), 7.26-7.20 (m, 1H),6.07 (s, 1H), 5.85 (s, 1H), 3.95 (s, 2H), 3.57-3.48 (m, 2H), 2.42 (s,3H), 1.28 (m, 2H) 7-((6-cyanopyridin-2-yl)methyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine- 3-carboxamide 21.23

382.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.31 (t, J = 5.3 Hz, 1H), 7.38- 7.28(m, 1H), 7.22 (t, J = 52 Hz, 2H), 6.08 (s, 1H), 4.06 (s, 2H), 2.73 (d, J= 4.6 Hz, 3H), 2.29 (s, 3H). 7-[[3-(difluoromethyl)-2-fluoro-phenyl]methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.24

362.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.31 (q, J = 4.7 Hz, 1H), 7.37 (td, J= 7.3, 1.8 Hz, 1H), 7.24 (td, J = 7.4, 1.8 Hz, 1H), 7.14 (t, J = 7.6 Hz,1H), 6.00 (s, 1H), 5.20 (brs, 1H), 4.53 (s, 2H), 3.90 (s, 2H), 2.73 (d,J = 4.8 Hz, 3H), 2.29 (d, J = 1.0 Hz, 3H). 7-[[2-fluoro-3-(hydroxymethyl)phenyl]methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide

Example 21.25:7-(3-cyclopropyl-2-fluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

To a solution of7-[(3-chloro-2-fluorophenyl)methyl]-N-ethyl-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(prepared in a similar manner as Example 21.14) (70 mg, 0.18 mmol) indioxane (2 mL) and water (0.5 mL) was added cyclopropylboronic acid (35mg, 0.41 mmol), palladium acetate (28 mg, 0.12 mmol) andtricyclohexylphosphine (21 mg). After stirring overnight at 90° C. undernitrogen atmosphere, the resulting mixture was concentrated undervacuum. The residue was purified by chromatography with 2% methanol indichloromethane. The crude product was purified by Prep-HPLC (SunFirePrep C₁₈ OBD Column, 5 um, 19×150 mm; mobile phase A, water with 10 mmolNH₄HCO₃ and mobile phase B, CH₃CN; 50.0% CH₃CN up to 82.0% in 10 min,down to 50.0% in 2 min; Detector, UV 254/220 nm) to afford7-[(3-cyclopropyl-2-fluorophenyl)methyl]-N-ethyl-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(16.8 mg, 24%) as a white solid. LCMS (ESI): [M+H]⁺=386.10; ¹H NMR (300MHz, CDCl₃) δ 7.26-6.96 (m, 2H), 6.96-6.78 (m, 1H), 6.05 (s, 1H), 5.85(br, 1H), 3.95 (s, 2H), 3.58-3.42 (m, 2H), 2.42 (s, 3H), 2.10-2.02 (m,1H), 1.28 (m, 3H), 1.00-0.94 (m, 2H), 0.73-0.68 (m, 2H).

Example 21.26:7-(3-cyano-2-fluorobenzyl)-N-ethyl-6-fluoro-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

Step 1:7-(3-cyano-2-fluorobenzyl)-N-ethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

To a solution of7-(chloromethyl)-N-ethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(prepared in a similar manner as Example 16.1, Step 5) (100 mg, 0.37mmol) in 1,4-dioxane/water (2 mL/0.5 mL) was added(3-cyano-2-fluorophenyl)boronic acid (121 mg, 0.73 mmol),[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (28 mg,0.04 mmol), and sodium carbonate (78 mg, 0.74 mmol). The reactionmixture was irradiated with microwave radiation for 45 min at 100° C.The resulting mixture was concentrated under vacuum and purified bychromatography with dichloromethane/methanol (30:1) to afford7-[(3-cyano-2-fluorophenyl)methyl]-N-ethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(69 mg, 53%) as a yellow solid. LCMS (ESI): [M+H]⁺=357.0.

Step 2:7-(3-cyano-2-fluorobenzyl)-N-ethyl-6-fluoro-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

To a solution of7-[(3-cyano-2-fluorophenyl)methyl]-N-ethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(30 mg, 0.08 mmol) in CH₃CN (3 mL) was added Selectfluor® (30 mg, 0.24mmol). The resulting solution was stirred for 1.5 h at 75° C. Theresulting mixture was cooled to room temperature and concentrated undervacuum, and the residue was purified by chromatography withdichloromethane/methanol (30:1) to afford7-[(3-cyano-2-fluorophenyl)methyl]-N-ethyl-6-fluoro-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(8 mg, 25%) as a white solid. LCMS (ESI): [M+H]⁺=375.0; ¹H NMR (300 MHz,CDCl₃) δ 7.73-7.65 (m, 2H), 7.58 (s, 1H), 7.36-7.31 (m, 1H), 4.20 (s,2H), 3.33-3.31 (m, 2H), 1.29-1.10 (m, 3H).

Example 21.27:7-(3-cyano-2-fluorobenzyl)-6-fluoro-N,N-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

Step 1:7-(chloromethyl)-6-fluoro-N,N-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

To a solution of7-(chloromethyl)-N,2-dimethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(from Example 16.1, Step 5) (500 mg, 1.84 mmol) in CH₃CN (10 mL) wasadded Selectfluor® (980 mg, 2.76 mmol) and the resulting solution wasstirred for 4 h at 75° C. The resulting mixture was concentrated undervacuum. The residue was purified by chromatography withdichloromethane/ethyl acetate (5:1) to afford7-(chloromethyl)-6-fluoro-N,2-dimethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(110 mg, 21%) as a light yellow solid. LCMS (ESI): [M+H]⁺=290.0.

Step 2:7-(3-cyano-2-fluorobenzyl)-6-fluoro-N,N-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

To a solution of7-(chloromethyl)-6-fluoro-N,2-dimethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(100 mg, 0.35 mmol) in 1,4-dioxane (2 mL) under nitrogen was added(3-cyano-2-fluorophenyl)boronic acid (86 mg, 0.52 mmol), sodiumcarbonate (74 mg, 0.70 mmol),[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (26 mg,0.04 mmol), and water (0.2 mL). The reaction mixture was irradiated withmicrowave radiation for 20 min at 120° C. The resulting solution wasextracted with ethyl acetate (3×20 mL), washed with brine, dried overanhydrous sodium sulfate, and concentrated under vacuum. The residue waspurified by chromatography with dichloromethane/ethyl acetate (2:3), toafford7-[(3-cyano-2-fluorophenyl)methyl]-6-fluoro-N,N-dimethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(18 mg, 14%) as a off-white solid. LCMS (ESI): [M+H]⁺=374.9; ¹H NMR (300MHz, CDCl₃) δ 7.56 (m, 2H), 7.21 (m, 1H), 5.97 (s, 1H), 4.09 (m, 2H),3.05 (m, 3H), 2.41 (s, 3H).

The following examples were prepared in a manner similar to Example21.26 and 21.27:

LCMS No. Structure/Name (M + H) ¹H NMR 21.28

388.9 ¹H NMR (300 MHz, CDCl₃) δ 7.56-7.50 (m, 2H), 7.23-7.19 (m, 1H),5.86 (s, 1H), 4.09 (s, 2H), 3.58-3.51 (m, 2H), 2.40 (s, 3H), 1.32-1.28(m, 3H) 7-(3-cyano-2-fluorobenzyl)-N-ethyl-6-fluoro-2-methyl-5-oxo-5H-thiazolo[3,2- a]pyrimidine-3-carboxamide 21.29

418.0 ¹H NMR (300 MHz, CDCl₃) δ 7.51 (m, 2H), 7.21 (m, 1H), 5.91 (s,1H), 4.10 (s, 2H), 3.05 (m, 3H), 2.41 (s, 3H) 6-fluoro-7-(2-fluoro-3-(trifluoromethyl)benzyl)-N,2-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

The following compounds were prepared using methods analogous to thosedescribed above:

LCMS No. Structure/Name (M + H) ¹H NMR 21.30

367.0 ¹H NMR (300 MHz, CD₃OD) δ 7.54 (m, 2H), 7.39 (m, 1H), 6.03 (s,1H), 4.09 (s, 2H), 3.39 (m, 2H), 2.39 (s, 6H), 1.22 (m, 3H)7-(5-cyano-2-methylbenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine- 3-carboxamide 21.31

371.0 ¹H NMR (300 MHz, CDCl₃) δ 7.66-7.58 (m, 2H), 7.25-7.20 (m, 1H),6.12 (s, 1H), 5.90- 5.80 (m, 1H), 3.96 (s, 2H), 3.60-3.50 (m, 2H), 2.45(s, 3H), 1.33-1.29 (m, 3H) 7-(5-cyano-2-fluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3- carboxamide 21.32

379.95 ¹H NMR (300 MHz, CDCl₃) δ 7.36-7.32 (m, 1H), 7.03-6.91 (m, 2H),5.99 (s, 1H), 5.87 (br, 1H), 3.99 (s, 2H), 3.57-3.48 (m, 2H), 2.41 (s,3H), 1.28 (m, 3H) 7-(2-chloro-5-fluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine- 3-carboxamide 21.33

357.0 ¹H NMR (300 MHz, CDCl₃) δ 9.66 (br, 1H), 8.02 (s, 1H), 7.58-7.55(m, 2H), 7.27 (s, 1H), 6.19 (s, 1H), 4.00 (s, 2H), 3.50-3.41 (m, 2H),1.27-1.17 (m, 3H) 7-(3-cyano-2-fluorobenzyl)-N-ethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.34

421.20 ¹H NMR (300 MHz, CDCl₃) δ 7.70-7.66 (m, 1H), 7.09-7.04 (m, 2H),5.95-5.92 (m, 2H), 4.08 (s, 2H), 3.56-3.47 (m, 2H), 2.41 (s, 3H),1.30-1.18 (m, 3H) N-ethyl-7-(5-fluoro-2-(trifluoromethyl)benzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.35

378.0 ¹H NMR (300 MHz, CDCl₃) δ 7.87-7.79 (m, 3H), 7.52-7.40 (m, 4H),5.95-5.84 (m, 1H), 5.81 (s, 1H), 4.36 (s, 2H), 3.66-3.47 (m, 2H), 2.37(s, 3H), 1.25-1.16 (t, 3H) N-ethyl-2-methyl-7-(naphthalen-1-ylmethyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3- carboxamide 21.36

360.0 ¹H NMR (300 MHz, CD₃OD) δ 7.19 (m, 1H), 6.94 (m, 2H), 5.95 (s,1H), 3.95 (s, 2H), 3.40 (m, 2H), 2.40 (s, 3H), 2.26 (s, 3H), 1.23 (m,3H) N-ethyl-7-(5-fluoro-2-methylbenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine- 3-carboxamide 21.37

371.0 ¹H NMR (400 MHz, CDCl₃) δ 7.54-7.47 (m, 2H), 7.19-7.14 (m, 1H),6.09 (s, 1H), 5.84 (br, 1H), 3.86 (s, 2H), 3.57-3.50 (m, 2H), 2.42 (s,3H), 1.27 (m, 3H) 7-(3-cyano-4-fluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3- carboxamide 21.38

382.20 ¹H NMR (400 MHz, CDCl₃) δ 7.98 (s, 1H), 7.37-7.30 (m, 2H),7.02-7.01 (m, 1H), 6.01 (s, 1H), 5.83 (s, 1H), 4.25 (s, 2H), 4.12 (s,3H), 3.51-3.50 (m, 2H), 2.45-2.35 (m, 3H), 1.27-1.15 (m, 3H)N-ethyl-2-methyl-7-((1-methyl-1H-indazol-4-yl)methyl)-5-oxo-5H-thiazolo[3,2- a]pyrimidine-3-carboxamide 21.39

421.0 ¹H NMR (300 MHz, CD₃OD) δ 7.29 (m, 2H), 7.09 (m, 2H), 6.13 (s,1H), 3.91 (s, 2H), 3.40 (m, 2H), 2.94 (s, 3H), 2.39 (s, 3H), 1.23 (m,3H) N-ethyl-2-methyl-7-(3- (methylsulfonamido)benzyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.40

421.20 ¹H NMR (300 MHz, CDCl₃) δ 7.81-7.78 (m, 1H), 7.69-7.67 (m, 1H),5.60 (s, 1H), 5.82 (s, 1H), 4.11 (s, 2H), 3.58-3.52 (m, 2H), 2.44 (s,3H), 1.31- 1.26 (m, 3H) 7-(5-cyano-2-(trifluoromethyl)benzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2- a]pyrimidine-3-carboxamide 21.41

362.0 ¹H NMR (300 MHz, CDCl₃) δ 7.13 (m, 3H), 5.99 (s, 1H), 5.87 (s,1H), 4.10 (s, 2H), 3.03 (s, 3H), 2.30 (s, 3H), 2.24 (s, 3H)7-(4-chloro-2-methylbenzyl)-N,2-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3- carboxamide 21.42

364.0 ¹H NMR (300 MHz, CDCl₃) δ 7.05-6.89 (m, 3H), 6.10 (s, 1H), 6.04(s, 1H), 3.88 (s, 2H), 3.55-3.46 (m, 2H), 2.36 (s, 3H), 1.29-1.27 (m,3H) 7-(2,5-difluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3- carboxamide 21.43

379.0 ¹H NMR (300 MHz, CDCl₃) δ 7.54-7.53 (m, 2H), 7.49-7.38 (m, 2H),6.06 (s, 1H), 5.89 (s, 1H), 3.88 (s, 2H), 3.56-3.49 (m, 2H), 2.19-2.09(m, 1H), 1.31-1.21 (m, 3H), 1.18-1.11 (m, 2H), 0.88-0.78 (m, 2H)7-(3-cyanobenzyl)-2-cyclopropyl-N-ethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3- carboxamide 21.44

346.0 ¹H NMR (400 MHz, CDCl₃) δ 7.48-7.46 (m, 1H), 7.30-7.21 (m, 1H),7.14-7.03 (m, 2H), 6.06 (s, 1H), 6.01 (s, 1H), 3.93 (s, 2H), 3.56-3.46(m, 2H), 2.38 (s, 3H), 1.30-1.25 (m, 3H)N-ethyl-7-(2-fluorobenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.45

364.0 ¹H NMR (400 MHz, CDCl₃) δ 7.11-6.99 (m, 3H), 6.04 (s, 1H), 5.90(s, 1H), 3.95 (s, 2H), 3.55-3.48 (m, 2H), 2.40 (s, 3H), 1.29-1.16 (m,3H) 7-(2,3-difluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3- carboxamide 21.46

346.0 ¹H NMR (300 MHz, CD₃OD) δ 7.36-7.29 (m, 1H), 7.13-6.94 (m, 3H),6.15 (s, 1H), 3.93 (s, 2H), 3.41 (m, 2H), 2.40 (s, 3H), 1.24 (m, 3H)N-ethyl-7-(3-fluorobenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide 21.47

366.1 ¹H NMR (400 MHz, DMSO- d₆) δ 8.29 (t, J = 4.8 Hz, 1H), 7.52 (dd, J= 7.2, 2.0 Hz, 1H), 7.39-7.28 (m, 2H), 6.17 (s, 1H), 2.73 (d, J = 4.7Hz, 3H), 2.29 (s, 3H). 7-[(3-chloro-4-fluoro-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide 21.48

382.0 ¹H NMR (400 MHz, DMSO- d₆) δ 8.32 (q, J = 4.7 Hz, 1H), 7.52-7.48(m, 2H), 7.39 (dd, J = 8.6, 2.6 Hz, 1H), 5.97 (s, 1H), 4.02 (s, 2H),2.73 (d, J = 4.8 Hz, 3H), 2.29 (s, 3H).7-[(2,5-dichlorophenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide 21.49

398.1 ¹H NMR (400 MHz, DMSO- d₆) δ 8.35-8.25 (m, 1H), 7.45 (t, J = 7.9Hz, 1H), 7.33 (dd, J = 9.9, 2.4 Hz, 2H), 7.27-7.19 (m, 1H), 6.16 (d, J =1.2 Hz, 1H), 3.93 (s, 2H), 2.73 (d, J = 4.6 Hz, 3H), 2.29 (s, 3H).N,2-dimethyl-5-oxo-7-[[3- (trifluoromethoxy)phenyl]methyl]thiazolo[3,2-a]pyrimidine-3-carboxamide 21.50

357.1 ¹H NMR (400 MHz, DMSO- d₆) δ 8.30 (d, J = 4.9 Hz, 1H), 7.92 (dd, J= 6.9, 2.2 Hz, 1H), 7.85 (ddd, J = 8.5, 4.8, 2.2 Hz, 1H), 7.44 (dd, J =9.7, 8.6 Hz, 1H), 6.11 (s, 1H), 3.97 (s, 2H), 2.73 (d, J = 4.7 Hz, 3H),2.29 (s, 3H). 7-[(5-cyano-2-fluoro-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide 21.51

373.0 ¹H NMR (400 MHz, DMSO- d₆) δ 8.31-8.25 (m, 1H), 7.91 (t, J = 1.8Hz, 1H), 7.76 (dt, J = 7.0, 1.6 Hz, 2H), 6.22 (s, 1H), 3.94 (s, 2H),2.74 (d, J = 4.7 Hz, 3H), 2.29 (s, 3H).7-[(3-chloro-5-cyano-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide 21.52

354.1 ¹H NMR (400 MHz, DMSO- d₆) δ 8.30 (q, J = 4.7 Hz, 1H), 7.20-7.14(m, 1H), 7.03 (dd, J = 6.8, 1.4 Hz, 2H), 6.91 (dt, J = 7.9, 1.5 Hz, 1H),6.08 (s, 1H), 3.80 (s, 2H), 2.73 (d, J = 4.7 Hz, 3H), 2.28 (s, 3H), 1.88(tt, J = 8.4, 5.1 Hz, 1H), 0.97- 0.88 (m, 2H), 0.68-0.61 (m, 2H).7-[(3-cyclopropylphenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide 21.53

350.1 ¹H NMR (400 MHz, DMSO- d₆) δ 8.31 (q, J = 4.7 Hz, 1H), 7.24 (tt, J= 8.8, 4.1 Hz, 2H), 7.15 (tt, J = 8.8, 3.6 Hz, 1H), 6.06 (s, 1H), 3.91(s, 2H), 2.73 (d, J = 4.7 Hz, 3H), 2.29 (s, 3H).7-[(2,5-difluorophenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide 21.54

350.1 ¹H NMR (400 MHz, DMSO- d₆) δ 8.30 (q, J = 4.7 Hz, 1H), 7.43-7.29(m, 2H), 7.15 (dd, J = 4.6, 2.2 Hz, 1H), 6.15 (s, 1H), 3.86 (s, 2H),2.78-2.68 (m, 3H), 2.34 (s, 3H).7-[(3,4-difluorophenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide 21.55

350.1 ¹H NMR (400 MHz, DMSO- d₆) δ 8.31 (t, J = 5.3 Hz, 1H), 7.38-7.28(m, 1H) 7.22-7.13 (m, 2H), 6.08 (s, 1H), 4.06 (s, 2H), 2.73 (d, J = 4.6Hz, 3H), 2.29 (s, 3H). 7-[(2,3-difluorophenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide 21.56

366.1 ¹H NMR (400 MHz, DMSO- d₆) δ 8.32 (q, J = 4.7 Hz, 1H), 7.46-7.41(m, 1H), 7.41-7.36 (m, 1H), 7.26 (dd, J = 8.3, 2.1 Hz, 1H), 6.06 (s,1H), 3.91 (s, 2H), 2.73 (d, J = 4.7 Hz, 3H), 2.29 (s, 3H).7-[(4-chloro-2-fluoro-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide 21.57

382.0 ¹H NMR (400 MHz, DMSO- d₆) δ 8.29 (d, J = 5.4 Hz, 1H), 7.61-7.55(m, 2H) 7.30 (dd, J = 8.3, 2.1 Hz, 1H), 6.19 (s, 1H), 3.88 (s, 2H), 2.73(d, J = 4.7 Hz, 3H), 2.29 (s, 3H).7-[(2,4-dichlorophenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide 21.58

346.1 ¹H NMR (400 MHz, DMSO- d₆) δ 8.29 (d, J = 5.2 Hz, 1H), 7.21 (t, J= 8.0 Hz, 1H), 7.09- 6.99 (m, 2H), 6.12 (s, 1H), 3.83 (s, 2H), 2.73 (dt,J = 4.8, 0.8 Hz, 3H), 2.29 (s, 3H), 2.23 (s, 3H).7-[(3-fluoro-4-methyl-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide 21.59

400.1 ¹H NMR (400 MHz, DMSO- d₆) δ 8.32-8.26 (m, 1H), 7.73 (dd, J = 7.1,2.2 Hz, 1H), 7.67 (ddd, J = 7.8, 4.9, 2.3 Hz, 1H), 7.45 (dd, J = 11.0,8.4 Hz, 1H), 6.19 (s, 1H), 3.96 (s, 2H), 2.73 (d, J = 4.6 Hz, 3H), 2.29(s, 3H). 7-[[4-fluoro-2- (trifluoromethyl)phenyl]methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide 21.60

372.1 ¹H NMR (400 MHz, DMSO- d₆) δ 8.36 (q, J = 4.7 Hz, 1H), 7.24 (dd, J= 8.5, 6.2 Hz, 1H), 6.96 (td, J = 8.5, 2.8 Hz, 1H), 6.78 (dd, J = 10.7,2.7 Hz, 1H), 5.92 (d, J = 0.7 Hz, 1H), 4.04 (s, 2H), 2.73 (d, J = 4.7Hz, 3H), 2.29 (s, 3H), 1.98 (ddd, J = 13.7, 8.6, 5.3 Hz, 1H), 0.94- 0.85(m, 2H), 0.69-0.60 (m, 2H). 7-[(2-cyclopropyl-4-fluoro-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2- a]pyrimidine-3-carboxamide 21.61

425.0 ¹H NMR (300 MHz, CDCl₃) δ 7.65 (m, 3H), 5.93 (s, 1H), 5.85 (s,1H), 4.72 (m, 1H), 4.57 (m, 1H), 3.96 (s, 2H), 3.52 (m, 2H), 3.13 (m,1H), 3.05 (m, 1H), 2.42 (s, 3H), 1.25 (m, 3H)7-(5-cyano-2-(2-fluoroethyl)benzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2- a]pyrimidine-3-carboxamide 21.62

386.9 ¹H NMR (300 MHz, DMSO- d₆) δ 8.42-8.39 (m, 1H), 7.93- 7.90 (m,1H), 7.78-7.76 (m, 1H), 7.57-7.52 (m, 1H), 6.02 (s, 1H), 4.11 (s, 2H),3.31-3.18 (m, 2H), 2.30 (s, 3H), 1.12- 1.07 (m, 3H)7-(2-chloro-3-cyanobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine- 3-carboxamide 21.63

392.0 ¹H NMR (300 MHz, CDCl₃) δ 7.04 (m, 2H), 5.94 (s, 1H), 5.82 (s,1H), 4.01 (s, 2H), 3.51 (m, 2H), 2.58 (m, 2H), 2.41 (s, 3H), 1.26 (m,3H), 1.15 (m, 3H) N-ethyl-7-(6-ethyl-2,3-difluorobenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine- 3-carboxamide 21.64

381.0 ¹H NMR (300 MHz, CDCl₃) δ 7.53-7.51 (m, 1H), 7.44 (s, 1H),7.33-7.26 (m, 1H), 5.89- 5.87 (m, 2H), 3.94(s, 2H), 3.56-3.49 (m, 2H),2.71-2.65 (m, 2H), 2.41 (s, 3H), 1.29- 1.23 (m, 3H), 1.21-1.17 (m, 3H)7-(5-cyano-2-ethylbenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3- carboxamide 21.65

386.10 ¹H NMR (300 MHz, CDCl₃) δ 7.27-7.00 (m, 1H), 6.92-6.68 (m, 2H),5.95 (s, 1H), 5.86 (br, 1H), 4.10 (s, 2H), 3.58-3.49 (m, 2H), 2.43 (s,3H), 1.84- 1.75 (m, 1H), 1.31-1.19 (m, 3H), 0.92-0.88 (m, 2H), 0.67-0.55 (m, 2H) 7-(2-cyclopropyl-5-fluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine- 3-carboxamide 21.66

393.0 ¹H NMR (300 MHz, CDCl₃) δ 7.47-7.44 (m, 1H), 7.32-7.19 (m, 2H),5.94 (s, 1H), 5.83- 5.81 (m, 1H), 4.16 (s, 2H), 3.56-3.52 (m, 2H), 2.41(s, 3H), 1.92-1.82 (m, 1H), 1.32- 1.23 (m, 3H), 1.02-0.96 (m, 2H),0.70-0.65 (m, 2H) 7-(5-cyano-2-cyclopropylbenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine- 3-carboxamide 21.67

388.0 ¹H NMR (300 MHz, CDCl₃) δ 7.16-7.11 (m, 1H), 6.93-6.83 (m, 2H),5.86 (s, 1H), 5.86 (s, 1H), 3.90 (s, 2H), 3.53-3.51 (m, 2H), 2.54-2.49(m, 2H), 2.42 (s, 3H), 1.59-1.51 (m, 2H), 1.29-1.24 (m, 3H), 0.96- 0.91(m, 3H) N-ethyl-7-(5-fluoro-2-propylbenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine- 3-carboxamide 21.68

364.1 ¹H NMR (400 MHz, DMSO- d₆) δ 8.31 (q, J = 4.6 Hz, 1H), 7.43 (tq, J= 7.4, 2.2 Hz, 2H), 7.26-7.18 (m, 1H), 6.04 (s, 1H), 5.48 (dd, J = 47.6,1.2 Hz, 2H), 3.95 (s, 2H), 2.73 (d, J = 4.7 Hz, 3H), 2.29 (s, 3H).7-[[2-fluoro-3-(fluoromethyl)phenyl]methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2- a]pyrimidine-3-carboxamide

Method 22 Example 22.1:N-ethyl-7-(1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

Step 1:N-ethyl-7-(1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

To a −78° C. solution ofN-ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(from Example 21.12) (200 mg, 0.48 mmol) in tetrahydrofuran (20 mL) wasadded n-butyllithium (2.5 M in hexanes; 1 mL). After 30 min at −78° C.,iodomethane (235 mg, 1.66 mmol) was added. The resulting solution wasstirred for 3 h at room temperature. The reaction was then quenched bywater (20 mL), extracted with dichloromethane (3×30 mL), washed withbrine, dried over sodium sulfate and concentrated in vacuo. The residuewas purified by chromatography with dichloromethane/methanol (50:1) toaffordN-ethyl-7-[1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(52.7 mg, 25%) as a white solid. LCMS (ESI): [M+H]⁺=428.0; ¹H NMR (300MHz, CDCl₃) δ 7.60-7.48 (m, 2H), 7.20-7.19 (m, 1H), 6.13 (s, 1H), 5.92(m, 1H), 4.42-4.34 (m, 2H), 3.56-3.48 (m, 2H), 2.40 (s, 3H), 1.64-1.62(m, 3H), 1.30-1.25 (m, 3H).

The following compound was prepared using methods analogous to thosedescribed above:

LCMS No. Structure/Name (M + H) ¹H NMR 22.2

428.0 ¹H NMR (300 MHz, CDCl₃) δ 7.55- 7.48 (m, 2H), 7.26-7.18 (m, 1H),6.05 (s, 1H), 3.97 (s, 2H), 3.77-3.68 (m, 0.5H), 3.54-3.45 (m, 0.5H),3.26-3.18 (m, 1H), 3.11 (s, 1H), 2.86 (s, 2H), 2.34 (s, 3H), 1.30-1.25(m, 2H), 1.17- 1.12 (m, 1H). N-ethyl-7-(2-fluoro-3-(trifluoromethyl)benzyl)-N,2-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3- carboxamide

Method 23 Example 23.1:3-((3-(2-cyanocyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile

Step 1:3-((3-bromo-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile

To a solution of3-bromo-7-(chloromethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(from Example 4.1, Step 6) (500 mg, 1.70 mmol) in 1,4-dioxane/H₂O (3/1mL) was added (3-cyanophenyl)boronic acid (300 mg, 2.04 mmol),tetrakis(triphenylphosphine)palladium (197 mg, 0.17 mmol) and potassiumphosphate (730 mg, 3.44 mmol). The resulting solution was stirredovernight at 80° C. After cooling down to room temperature, theresulting mixture was washed with brine (30 mL), extracted withdichloromethane (3×20 mL), dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by silica gelchromatography with ethyl acetate/petroleum ether (1:2) to afford of3-([3-bromo-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-7-yl]methyl)benzonitrileas a light brown solid (522 mg, 85%). LCMS [M+H]⁺=360.0, 362.0.

Step 2: ethyl2-(7-(3-cyanobenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)cyclopropanecarboxylate

To a solution of3-([3-bromo-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-7-yl]methyl)benzonitrile(200 mg, 0.56 mmol) in CH₃CN/H₂O (3/1 mL) was added ethyl2-(tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropane-1-carboxylate (fromExample 4.18, Step 1) (267 mg, 1.11 mmol),[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (42 mg,0.06 mmol) and potassium carbonate (154 mg, 1.11 mmol). The reactionmixture was heated under microwave irradiation for 1.5 h at 120° C. Theresulting mixture was washed with brine (20 mL), extracted withdichloromethane (3×20 mL), dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by chromatographywith dichloromethane/methanol (50:1) to afford ethyl7-[(3-cyanophenyl)methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxylate(68 mg 35%) as a brown solid. LCMS (ESI): [M+H]⁺=394.0.

Step 3:2-(7-(3-cyanobenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)cyclopropanecarboxylicacid

To a solution of7-[(3-cyanophenyl)methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropane-1-carboxylate(68 mg, 0.17 mmol) in THF/H₂O (2/1 mL) was added lithium hydroxide (73mg, 1.7 mmol). The resulting solution was stirred overnight at roomtemperature. The pH of the solution was adjusted to pH 7 withhydrochloric acid solution (aq.) and the resulting mixture was extractedwith ethyl acetate (3×20 mL), washed with brine, dried over sodiumsulfate and concentrated under vacuum to afford2-[7-[(3-cyanophenyl)methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropane-1-carboxylicacid (80 mg, crude) as a brown solid. The crude product was used in nextstep without further purification. LCMS (ESI): [M+H]⁺=366.0.

Step 4:2-(7-(3-cyanobenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)cyclopropanecarboxamide

To a solution of2-[7-[(3-cyanophenyl)methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropane-1-carboxylicacid (80 mg, 0.22 mmol) in tetrahydrofuran (5 mL) was added propan-2-ylchloroformate (40.4 mg, 0.33 mmol), triethylamine (44 mg, 0.43 mmol) andammonia (2 mL, 25 weight % in water). The resulting solution was stirredfor 1 h at room temperature and concentrated under vacuum, and theresidue was purified by chromatography with dichloromethane/methanol(30:1) to afford2-[7-[(3-cyanophenyl)methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropane-1-carboxamide(21 mg, 26%) as a brown solid. LCMS (ESI): [M+H]⁺=364.9.

Step 5:3-((3-(2-cyanocyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile

To a solution of2-[7-[(3-cyanophenyl)methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropane-1-carboxamide(17 mg, 0.05 mmol) in methylene chloride (10 mL) was added1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) and ethoxyphosphonoyldichloride (0.25 mL). The resulting solution was stirred for 1 h at roomtemperature. The reaction was then quenched by water (30 mL), extractedwith dichloromethane (3×20 mL), washed with brine, and concentratedunder vacuum. The residue was purified on a silica gel column elutedwith dichloromethane/methanol (50:1) to afford3-[[3-(2-cyanocyclopropyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-7-yl]methyl]benzonitrile(12.6 mg, 78%) as a off-white solid. LCMS (ESI): [M+H]⁺=347.0; ¹H NMR(300 MHz, CDCl₃) δ 7.69-7.60 (m, 3H), 7.53-7.47 (m, 1H), 6.16 (s, 1H),3.94 (s, 2H), 2.92-2.88 (m, 1H), 2.39 (s, 3H), 1.96-1.92 (m, 1H),1.81-1.74 (m, 1H), 1.59-1.52 (m, 1H).

Example 23.2:3-((3-(2-cyanocyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)-2-fluorobenzonitrile

Step 1:3-((3-bromo-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)-2-fluorobenzonitrile

A mixture of3-bromo-7-(chloromethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(from Example 4.1, Step 6) (500 mg, 1.70 mmol), potassium phosphate (733mg, 3.45 mmol), tetrakis(triphenylphosphine)palladium (198 mg, 0.17mmol), (3-cyano-2-fluorophenyl)boronic acid (339 mg, 2.06 mmol),1,4-dioxane (6 mL) and water (1 mL) was stirred overnight at 80° C. in a30-mL sealed tube. The resulting mixture was diluted with brine andextracted with 3×30 mL of dichloromethane, and the combined organiclayers were washed with brine, dried over anhydrous sodium sulfate, andconcentrated under vacuum. The residue was purified by silica gelchromatography with dichloromethane/methanol (80:1) to afford3-([3-bromo-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-7-yl]methyl)-2-fluorobenzonitrile(70 mg, 11%) as a yellow solid. LCMS (ESI): [M+H]⁺=378.

Step 2:3-((3-(2-cyanocyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)-2-fluorobenzonitrile

To a solution of3-([3-bromo-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-7-yl]methyl)-2-fluorobenzonitrile(100 mg, 0.26 mmol) in 1,4-dioxane/H₂O (2 mL/0.5 mL) addedtetrakis(triphenylphosphine)palladium (31 mg, 0.03 mmol), potassiumphosphate (112 mg, 0.53 mmol), and potassiumtrans-2-cyanocyclopropyltrifluoroborate (prepared in a manner similar toExample 4.1, Step 2) (92 mg, 0.53 mmol). The resulting solution wasstirred for 3 h at 80° C. After filtration to remove solids, thefiltrate was concentrated under vacuum and purified by chromatographywith dichloromethane/methanol (100:1) to afford3-[[3-(2-cyanocyclopropyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-7-yl]methyl]-2-fluorobenzonitrile(16 mg, 17%) as a white solid. LCMS (ESI): [M+H]⁺=364.9; ¹H NMR (300MHz, CDCl₃) δ 7.60-7.54 (m, 2H), 7.28-7.21 (m, 1H), 6.03 (s, 1H), 3.94(s, 2H), 3.00-2.94 (m, 1H), 2.43 (s, 3H), 1.90-1.80 (m, 1H), 1.79-1.70(m, 1H), 1.45-1.35 (m, 1H).

The following example was prepared in a manner similar to Example 23.1and 23.2:

LCMS No. Structure/Name (M + H) ¹H NMR 23.3

348.05 ¹H NMR (300 MHz, CDCl₃) δ 7.95-7.92 (m, 1H), 7.77-7.69 (m, 2H),6.21 (s, 1H), 4.86 (s, 2H), 2.86-2.98 (m, 1H), 2.39 (s, 3H), 1.28-2.02(m, 3H) 6-((3-(2-cyanocyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7- yl)methyl)picolinonitrile

The following compound was prepared using methods analogous to thosedescribed above:

LCMS No. Structure/Name (M + H) ¹H NMR 23.4

753.15 ¹H NMR (300 MHz, CDCl₃) δ 7.62 (m, 1H), 7.50 (s, 1H), 6.96 (m,1H), 6.01 (s, 1H), 3.91 (s, 3H), 3.88 (s, 2H), 3.01 (m, 1H), 2.41 (s,3H), 1.81 (m, 1H), 1.74 (m, 1H), 1.41 (m, 1H)3-((3-(2-cyanocyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7- yl)methyl)-4-methoxybenzonitrile

Method 24 Example 24.1:2-methyl-3-(pyrimidin-5-yl)-7-(3-(trifluoromethyl)benzyl)-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-bromo-2-methyl-7-[[3-(trifluoromethyl)phenyl]methyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(prepared in a manner similar to Example 21.1, Step 1) (60 mg, 0.15mmol) in 1,4-dioxane (2 mL) was added (pyrimidin-5-yl)boronic acid (37mg, 0.30 mmol), potassium phosphate (64 mg, 0.30 mmol),tetrakis(triphenylphosphine)palladium (17 mg, 0.01 mmol) and water (0.2mL). The resulting solution was stirred for 3 h at 90° C. in an oilbath. The resulting solution was quenched with water (10 mL), extractedwith dichloromethane (3×20 mL), washed with brine, dried over anhydroussodium sulfate and concentrated under vacuum. The residue was thenpurified by chromatography with ethyl acetate/petroleum ether (1:2.5) toafford2-methyl-3-(pyrimidin-5-yl)-7-[[3-(trifluoromethyl)phenyl]methyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(27.7 mg, 46%) as a off-white solid. LCMS (ESI): [M+H+41]⁺ 444.1; ¹H NMR(300 MHz, CD₃OD) δ 9.18 (s, 1H), 8.82 (s, 2H), 7.65-7.55 (m, 4H), 6.11(s, 1H), 4.03 (s, 2H), 2.28 (s, 3H).

The following examples were prepared in a manner similar to Example24.1:

LCMS No. Structure/Name (M + H) ¹H NMR 24.2

421.0 ¹H NMR (300 MHz, CDCl₃) δ 9.25 (s, 1H), 8.70 (s, 2H), 7.56-7.50(m, 2H), 7.22-7.19 (m, 1H), 5.99 (s, 1H), 3.99 (s, 2H), 2.27 (s, 3H)7-(2-fluoro-3-(trifluoromethyl)benzyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2- a]pyrimidin-5-one 24.3

378.0 ¹H NMR (300 MHz, CDCl₃) δ 9.25 (s, 1H), 8.69 (s, 2H), 7.60-7.53(m, 2H), 7.23-7.21 (m, 1H), 6.00 (s, 1H), 3.96 (s, 2H), 2.26 (s, 3H)2-fluoro-3-((2-methyl-5-oxo-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-7- yl)methyl)benzonitrile 24.4

340.0 ¹H NMR (300 MHz, CDCl₃) δ 7.60-7.51 (m, 2H), 7.24-7.18 (m, 1H),5.96 (s, 1H), 3.90 (s, 2H), 2.36 (s, 3H), 2.26-2.25 (m, 1H), 1.10-1.03(m, 2H), 0.69-0.65 (m, 2H) 3-((3-cyclopropyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)-2- fluorobenzonitrile

The following compounds were prepared using methods analogous to thosedescribed above:

LCMS No. Structure/Name (M + H) ¹H NMR 24.5

386.0 ¹H NMR (300 MHz, CDCl₃) δ 9.22 (s, 2H), 8.66 (s, 2H), 8.49 (s,1H), 8.03 (m, 1H), 7.95 (m, 1H), 7.76-7.62 (m, 2H), 5.87 (s, 1H), 4.32(s, 2H), 2.26 (s, 3H) 7-(isoquinolin-4-ylmethyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5- one 24.6

401.15 ¹H NMR (300 MHz, CDCl₃) δ 9.26 (s, 1H), 8.76 (s, 2H), 7.68-7.41(m, 3H), 7.29-7.26 (m, 1H), 6.02 (s, 1H), 3.92 (s, 2H), 2.27 (s, 3H)3-((2-methyl-5-oxo-3-(pyrimidin-5-yl)-5H- thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile 24.7

382.95 ¹H NMR (300 MHz, CD₃OD) δ 9.21 (s, 1H), 8.81 (s, 2H), 7.07-6.95(m, 3H), 5.92 (s, 1H), 3.91 (s, 2H), 3.79 (s, 3H), 2.17 (s, 3H)7-(5-fluoro-2-methoxybenzyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5- one 24.8

366.0 ¹H NMR (300 MHz, CDCl₃) δ 7.58-7.52 (m, 3H), 7.24-7.19 (m, 1H),6.52-6.50 (m, 2H), 6.01 (s, 1H), 3.95 (s, 2H), 2.30 (s, 3H)2-fluoro-3-((3-(furan-2-yl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7- yl)methyl)benzonitrile 24.9

415 ¹H NMR (300 MHz, CDCl₃) δ 7.87-7.84 (m, 3H), 7.56-7.53 (m, 1H), 6.04(s, 1H), 3.95 (s, 2H), 3.06 (s, 3H), 2.35 (s, 3H) 3-bromo-2-methyl-7-(3-(methylsulfonyl)benzyl)-5H-thiazolo[3,2- a]pyrimidin-5-one

Method 25 Example 25.1:7-(3-cyano-2-fluorobenzyl)-2-methyl-5-oxo-N-(2,2,2-trifluoroethyl)-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

Step 1: ethyl7-(3-cyano-2-fluorobenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxylate

To a solution of ethyl7-(chloromethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxylate(500 mg, 1.74 mmol) in dioxane (2 mL) and water (0.5 mL) was added(3-cyano-2-fluorophenyl)boronic acid (375 mg, 2.27 mmol), sodiumcarbonate (370 mg, 3.49 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (77 mg,0.11 mmol). After stirring 20 minutes at 120° C. under nitrogenatmosphere, the resulting mixture was concentrated under vacuum. Theresidue was purified by chromatography with 10% ethyl acetate indichloromethane to afford ethyl7-[(3-cyano-2-fluorophenyl)methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxylate(23.1 mg, 18%) as a white solid. LCMS (ESI): [M+H]⁺=372.0; ¹H NMR (300MHz, CDCl₃) δ 7.72-7.66 (m, 2H), 7.36-7.31 (m, 1H), 6.19 (s, 1H),4.44-4.37 (m, 2H), 4.06 (s, 2H), 2.43 (s, 3H), 1.36 (m, 3H).

Step 2:7-(3-cyano-2-fluorobenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxylicacid

To a solution of ethyl7-[(3-cyano-2-fluorophenyl)methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxylate(prepared in a manner similar to Example 21.1) (100 mg, 0.27 mmol) intetrahydrofuran (3 mL) was added lithium hydroxide (64 mg, 2.67 mmol) inwater (3 mL). The resulting solution stirred for 3 days at roomtemperature. The reaction mixture was diluted with dichloromethane (20mL) and water (5 mL). The pH value of the water layer was adjusted to pH6 with hydrogen chloride. The resulting solution was extracted withdichloromethane (3×10 mL), washed with brine, dried over anhydroussodium sulfate and concentrated under vacuum to afford7-[(3-cyano-2-fluorophenyl)methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxylicacid (22 mg, 24%) as a brown solid. The crude product was used in nextstep without further purification. LCMS (ESI): [M+H]⁺=344.0.

Step 3:7-(3-cyano-2-fluorobenzyl)-2-methyl-5-oxo-N-(2,2,2-trifluoroethyl)-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

To a solution of7-[(3-cyano-2-fluorophenyl)methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxylicacid (60 mg, 0.17 mmol) in N,N-dimethylformamide (9 mL) was added2,2,2-trifluoroethan-1-amine (36 mg, 0.36 mmol), N-hydroxybenzotriazole(36 mg, 0.27 mmol), N,N-diisopropylethylamine (66 mg, 0.51 mmol) and1,1′-thiocarbonyldiimidazole (48 mg, 0.27 mmol). After stirred for 5 hat room temperature, the mixture was diluted with water (5 mL). Theresulting solution was extracted with dichloromethane (20 mL×3), washedwith brine, dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified by chromatography with 1% methanol indichloromethane. The crude product was purified by Prep-HPLC (SunFirePrep C₁₈ OBD Column, 5 um, 19×150 mm; mobile phase, water with 10 mmolNH₄HCO₃ and CH₃CN (50.0% CH₃CN up to 82.0% in 10 min, down to 50.0% in 2min); Detector, UV 254/220 nm) to afford7-[(3-cyano-2-fluorophenyl)methyl]-2-methyl-5-oxo-N-(2,2,2-trifluoroethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(20.8 mg, 28%) as a white solid. LCMS (ESI): [M+H]⁺ 424.95; ¹H NMR (300MHz, CD₃OD) δ 7.72-7.66 (m, 2H), 7.36-7.31 (m, 1H), 6.19 (s, 1H),4.15-4.06 (m, 4H), 2.40 (s, 3H).

The following example was prepared in a manner similar to Example 25.1:

LCMS No. Structure/Name (M + H) ¹H NMR 25.2

424.95 (300 MHz, DMSO-d₆) δ 9.15 (m, 1H), 7.75-7.68 (m, 2H), 7.42-7.37(m, 1H), 6.16 (s, 1H), 4.32 (m, 2H), 4.03 (s, 2H), 2.31 (s, 3H)N-(cyanomethyl)-7-(2-fluoro-3- (trifluoromethyl)benzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3- carboxamide

Method 26 Example 26.1:7-(3-cyanobenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile

Step 1:7-(3-cyanobenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile

To a solution of3-([3-bromo-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-7-yl]methyl)benzonitrile(from Example 21.1, Step 1) (100 mg, 0.28 mmol) in N,N-dimethylformamide(10 mL) under inert atmosphere was added copper cyanide (49 mg, 0.55mmol). The resulting solution was stirred for 1 h at 100° C. Aftercooling to room temperature, the reaction mixture was concentrated undervacuum. The residue was purified by chromatography withdichloromethane/methanol (50:1) to afford7-[(3-cyanophenyl)methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carbonitrile(8.4 mg, 10%) as a off-white solid. LCMS (ESI): [M+H]⁺=306.9; ¹H NMR(300 MHz, CDCl₃) δ 7.60-7.56 (m, 2H), 7.51-7.41 (m, 2H), 6.17 (s, 1H),3.91 (s, 2H), 2.65 (s, 3H).

The following example was prepared in a manner similar to Example 26.1:

LCMS No. Structure/Name (M + H) ¹H NMR 26.2

368.0 ¹H NMR (300 MHz, CDCl₃) δ 7.57-7.48 (m, 2H), 7.23-7.21 (m, 1H),6.16 (s, 1H), 3.98 (s, 2H), 2.65 (s, 3H)7-(2-fluoro-3-(trifluoromethyl)benzyl)-2- methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile

The following compounds were prepared using methods analogous to thosedescribed herein.

LCMS No. Structure/Name (M + H) ¹H NMR 27.1

347 ¹H NMR (300 MHz, CDCl₃) δ 7.01-6.87 (m, 4H), 6.52 (s, 1H), 4.95 (s,2H), 3.96-3.91 (m, 2H), 3.77-3.66 (m, 1H), 2.98-2.64 (m, 3H), 2.28-2.11(m, 1H) 10-(4-fluorophenoxymethyl)-3- (hydroxymethyl)-7-thia-1,9-diazatricyclo[6.4.0.0{circumflex over ( )}[2,6]]dodeca-2(6),8,10-trien-12-one 27.2

361.10 ¹H NMR (300 MHz, CDCl₃) δ 7.02-6.88 (m, 4H), 6.48 (s, 1H), 4.94(s, 2H), 3.95-3.91 (m, 1H), 3.68-3.62 (m, 2H), 2.99-2.91 (m, 1H),2.85-2.69 (m, 2H), 2.30-2.24 (m, 1H), 2.00-1.89 (m, 2H)10-(4-Fluorophenoxymethyl)-3-(2- hydroxyethyl)-7-thia-1,9-diazatricyclo[6.4.0.0{circumflex over ( )}[2,6]]dodeca-2(6),8,10-trien-12-one 27.3

396.1 7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-methylsulfonyl-thiazolo[3,2- a]pyrimidin-5-one 27.4

388.15 ¹H NMR (400 MHz, CD₃OD) δ 7.94 (s, 1H), 6.70 (s, 1H), 5.93 (s,1H), 5.36 (s, 2H), 3.88-3.76 (m, 3H), 3.02-2.40 (m, 4H)3-(hydroxymethyl)-10-[[3- (trifluoromethyl)-1H-pyrazol-1-yl]methyl]-7-thia-1,9- diazatricyclo[6.4.0.0{circumflex over( )}[2,6]]dodeca- 2(6),8,10-trien-12-one 27.5

381.00 ¹H NMR (300 MHz, CD₃OD) δ 6.32 (s, 1H), 5.72 (s, 1H), 5.41 (m,2H), 3.54-3.28 (m, 2H), 2.93-2.87 (m, 2H), 2.54-2.45 (m, 2H), 1.95- 1.86(m, 1H), 1.05-0.99 (m, 2H), 0.77-0.72 (m, 2H)10-{[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-7-thia-1,9- diazatricyclo[6.4.0.0{circumflexover ( )}{2,6}]dodeca- 2(6),8,10-trien-12-one 27.6

381.00 ¹H NMR (300 MHz, CD₃OD) δ 6.58 (s, 1H), 5.58 (s, 1H), 5.21 (m,2H), 3.54-3.28 (m, 2H), 2.93-2.87 (m, 2H), 2.59-2.41 (m, 2H), 2.01- 1.93(m, 1H), 0.98-0.96 (m, 2H), 0.79-0.77 (m, 2H)10-{[3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-7-thia-1,9- diazatricyclo[6.4.0.0{circumflexover ( )}{2,6}]dodeca- 2(6),8,10-trien-12-one 27.7

409.1 ¹H NMR (300 MHz, CDCl₃) δ 6.17 (s, 1H), 5.65 (s, 1H), 5.33 (s,2H), 2.85 (m, 2H), 2.38 (m, 2H), 1.75 (m, 1H), 1.50 (s, 6H), 1.01 (m,2H), 0.75 (m, 2H) 10-{[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-3,3-dimethyl- 7-thia-1,9-diazatricyclo[6.4.0.0{circumflex over ( )}{2,6}]dodeca-2(6),8,10-trien-12-one 27.8

409.0 ¹H NMR (300 MHz, CDCl₃) δ 6.34 (s, 1H), 5.51 (s, 1H), 5.23 (s,2H), 2.85 (m, 2H), 2.36 (m, 2H), 1.94 (m, 1H), 1.49 (s, 6H), 0.98 (m,2H), 0.77 (m, 2H) 10-{[3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-3,3-dimethyl- 7-thia-1,9-diazatricyclo[6.4.0.0{circumflex over ( )}{2,6}]dodeca-2(6),8,10-trien-12-one 27.9

437.0 ¹H NMR (300 MHz, CD₃OD) δ 7.30 (s, 1H), 5.88 (s, 1H), 5.50 (s,2H), 2.90 (m, 2H), 2.39 (m, 2H), 1.50 (s, 6H)10-{[3,5-bis(trifluoromethyl)-1H- pyrazol-1-yl]methyl}-3,3-dimethyl-7-thia-1,9- diazatricyclo[6.4.0.0{circumflex over ( )}{2,6}]dodeca-2(6),8,10-trien-12-one 27.10

341.9 ¹H NMR (400 MHz, CDCl₃) δ 7.58-7.54 (m, 2H), 7.26-7.22 (m, 1H),6.10 (s, 1H), 3.97 (s, 2H), 2.46 (s, 3H), 2.36 (s, 3H)3-((3-acetyl-2-methyl-5-oxo-5H- thiazolo[3,2-a]pyrimidin-7-yl)methyl)-2-fluorobenzonitrile 27.11

387.0 ¹H NMR (300 MHz, CDCl₃) δ 7.60-7.48 (m, 2H), 7.28-7.19 (m, 1H),6.17 (s, 1H), 5.83 (m, 1H), 5.08-5.03 (m, 1H), 4.00 (s, 2H), 2.40 (s,3H), 1.56-1.49 (m, 3H) 7-(2-fluoro-3-(trifluoromethyl)benzyl)-3-(1-hydroxyethyl)-2-methyl-5H- thiazolo[3,2-a]pyrimidin-5-one(enantiomer 1) 27.12

387.0 ¹H NMR (300 MHz, CDCl₃) δ 7.60-7.48 (m, 2H), 7.22-7.19 (m, 1H),6.16 (s, 1H), 5.84 (m, 1H), 5.08-5.02 (m, 1H), 4.00 (s, 2H), 2.42 (s,3H), 1.56-1.49 (m, 3H) 7-(2-fluoro-3-(trifluoromethyl)benzyl)-3-(1-hydroxyethyl)-2-methyl-5H- thiazolo[3,2-a]pyrimidin-5-one (enantiomer2) 27.13

323.95 ¹H NMR (300 MHz, CDCl₃) δ 7.59-7.51 (m, 3H), 7.46-7.41 (m, 1H),6.10 (s, 1H), 3.93 (s, 2H), 2.47 (s, 3H), 2.37 (s, 3H)3-((3-acetyl-2-methyl-5-oxo-5H- thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile 27.14

273.10 ¹H NMR (300 MHz, CDCl₃) δ 7.57-7.48 (m, 2H), 7.26-7.19 (m, 1H),6.12 (s, 1H), 4.74 (s, 2H), 4.42 (br, 1H), 3.99 (s, 2H), 2.42 (s, 3H)7-(2-fluoro-3-(trifluoromethyl)benzyl)-3- (hydroxymethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 27.15

386.0 ¹H NMR (300 MHz, CDCl₃) δ 7.61-7.47 (m, 2H), 7.26-7.19 (m, 1H),6.04 (s, 1H), 4.06 (s, 2H), 3.96 (s, 2H), 2.46 (s, 3H), 2.43 (s, 3H)7-(2-fluoro-3-(trifluoromethyl)benzyl)-2-methyl-3-((methylamino)methyl)-5H- thiazolo[3,2-a]pyrimidin-5-one

Example 12:3-[2-(Hydroxymethyl)cyclopropyl]-2-methyl-7-[3-(trifluoromethyl)phenoxy]thiazolo[3,2-a]pyrimidin-5-one

Step 1: 7-Hydroxy-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of 5-methyl-1,3-thiazol-2-amine (10 g, 87.6 mmol) inxylene (300 mL) was added 1,3-dimethyl propanedioate (23 g, 174 mmol),and stirred overnight at 150° C. The resulting mixture was concentratedin vacuo to afford7-hydroxy-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (14.6 g, 91%)as a light brown solid. LCMS (ESI): M+H⁺=183.0;

Step 2: 7-Chloro-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of7-hydroxy-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (30 g, 165mmol) in phosphorus oxychloride (250 mL, 2.68 mol) was stirred for 5 hat 110° C. The resulting solution was concentrated in vacuo. The residuewas purified by chromatography on silica gel eluting withdichloromethane/ethyl acetate (30/1) to afford7-chloro-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (2.34 g, 7%) asa yellow solid. LCMS (ESI): M+H⁺=201.0.

Step 3:2-Methyl-7-(3-(trifluoromethyl)phenoxy)-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of 7-chloro-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(500 mg, 2.50 mmol) in N,N-dimethylformamide (50 mL) was added3-(trifluoromethyl)phenol (808 mg, 5 mmol) and potassium carbonate (1.03g, 7.5 mmol). The resulting solution was stirred overnight at 100° C.and then concentrated in vacuo. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(50/1) to afford2-methyl-7-(3-(trifluoromethyl)phenoxy)-5H-thiazolo[3,2-a]pyrimidin-5-one(500 mg, 61%) as a yellow solid. LCMS (ESI): M+H⁺=327.0.

Step 4:3-Bromo-2-methyl-7-[3-(trifluoromethyl)phenoxy]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a solution of2-methyl-7-[3-(trifluoromethyl)phenoxy]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(500 mg, 1.53 mmol) in tetrahydrofuran (30 mL) was dropwise addedn-butyllithium (1.5 mL, 2.5 mol/L) at −78° C. under an inert atmosphereof nitrogen, and the reaction was stirred for 30 mins at −78° C.1-Bromopyrrolidine-2,5-dione (300 mg, 1.69 mmol) was added at −78° C.and the resulting solution was raised slowly to room temperature. Thereaction was quenched by 30 mL of water, then extracted and concentratedin vacuo. The residue was purified by chromatography on silica geleluting with dichloromethane/petroleum ether (10/1) to afford3-bromo-2-methyl-7-[3-(trifluoromethyl)phenoxy]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(100 mg, 13%) as an off-white solid. LCMS (ESI): M+H⁺=405.0.

Step 5:3-[2-(Hydroxymethyl)cyclopropyl]-2-methyl-7-[3-(trifluoromethyl)phenoxy]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-bromo-2-methyl-7-[3-(trifluoromethyl)phenoxy]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(30 mg, 0.07 mmol) in acetonitrile/water (2 mL/0.5 mL) was addedbis(diphenylphosphino)ferrocene]palladium(II) dichloride (6 mg, 0.01mmol), sodium carbonate (16 mg, 0.15 mmol), and potassiumtrans-2-(hydroxymethyl)cyclopropyltrifluoroborate (26 mg, 0.15 mmol).The reaction mixture was irradiated with microwave radiation for 90 minat 120° C. and then concentrated in vacuo. The residue was purified byflash chromatography on silica gel eluting with dichloromethane/methanol(50/1) to afford3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-7-[3-(trifluoromethyl)phenoxy]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(1.2 mg, 4%) as an off-white solid. LCMS (ESI): M+H⁺=396.9; ¹H NMR (300MHz, CDCl₃) δ 7.57-7.52 (m, 2H), 7.40 (s, 1H), 7.35-7.31 (m, 1H), 5.58(s, 1H), 4.08-4.05 (m, 1H), 3.12-3.07 (m, 1H), 2.38 (s, 3H), 2.29-2.26(m, 1H), 1.28-1.26 (m, 1H), 1.06-0.99 (m, 2H).

Example 24:3-[2-(Hydroxymethyl)cyclopropyl]-2-methyl-7-[[4-(trifluoromethyl)thiazol-2-yl]methyl]thiazolo[3,2-a]pyrimidin-5-one

Step 1: Methyl2-[3-bromo-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-7-yl]acetate

To a solution of3-bromo-7-(chloromethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(19.4 g, 66.1 mmol) in methanol (200 mL) was added[1,1″-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (5.0 g,6.83 mmol) and triethylamine (20 g, 197 mmol), and the reaction wasplaced under an atmosphere of CO (g) at 5 atm. The resulting solutionwas stirred for 12 h at room temperature and concentrated in vacuo. Theresidue was purified by flash chromatography on silica gel eluting withethyl acetate/petroleum ether (1/3) to afford methyl2-[3-bromo-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-7-yl]acetate(12.4 g, 59%) as a yellow solid. LCMS (ESI): M+H⁺=317.0.

Step 2:2-[3-Bromo-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-7-yl]acetamide

To a solution of methyl2-[3-bromo-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-7-yl]acetate(3 g, 9.46 mmol) in methanol (20 mL) was added NH₃ in methanol (40 mL, 5mol/L). The reaction tube was sealed and the resulting solution wasstirred for 6 h at 60° C. and then concentrated in vacuo. The residuewas purified by flash chromatography on silica gel eluting withdichloromethane/methanol (5/1) to afford2-[3-bromo-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-7-yl]acetamide(689 mg, 24%) as a brown solid. LCMS (ESI): M+H⁺=302.0.

Step 3:2-[3-Bromo-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-7-yl]ethanethioamide

To a solution of2-[3-bromo-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-7-yl]acetamide(689 mg, 2.28 mmol) in tetrahydrofuran (20 mL) was added2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (2.8g, 6.92 mmol). The resulting solution was stirred for 1 h at 65° C. andthen concentrated in vacuo. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/ethyl acetate(3/1) to afford2-[3-bromo-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-7-yl]ethanethioamide(334 mg, 46%) as a yellow solid. LCMS (ESI): M+H⁺=318.0.

Step 4:3-Bromo-2-methyl-7-[[4-(trifluoromethyl)-1,3-thiazol-2-yl]methyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a solution of2-[3-bromo-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-7-yl]ethanethioamide(200 mg, 0.63 mmol) in ethanol (10 mL) was added3-bromo-1,1,1-trifluoropropan-2-one (180 mg, 0.94 mmol). The resultingsolution was stirred for 1 h at 100° C., and the resulting mixture wasconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel eluting with dichloromethane/ethyl acetate (40/1) toafford3-bromo-2-methyl-7-[[4-(trifluoromethyl)-1,3-thiazol-2-yl]methyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(164 mg, 64%) as a yellow solid. LCMS (ESI): M+H⁺=410.0.

Step 5:3-[2-(Hydroxymethyl)cyclopropyl]-2-methyl-7-[[4-(trifluoromethyl)-1,3-thiazol-2-yl]methyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-bromo-2-methyl-7-[[4-(trifluoromethyl)-1,3-thiazol-2-yl]methyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(164 mg, 0.40 mmol) in acetonitrile/water (2 mL/0.5 mL) was addedpotassium trans-2-(hydroxymethyl)cyclopropyltrifluoroborate (143 mg,0.80 mmol), [1,1″-bis(diphenylphosphino)ferrocene]palladium(II)dichloride (30 mg, 0.04 mmol), and sodium carbonate (85 mg, 0.80 mmol).The reaction mixture was irradiated with microwave radiation for 1.5 hat 120° C., and the resulting mixture was concentrated in vacuo. Theresidue was purified by flash chromatography on silica gel eluting withdichloromethane/methanol (50/1) to afford3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-7-[[4-(trifluoromethyl)-1,3-thiazol-2-yl]methyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(7.7 mg, 5%) as an off-white solid. LCMS (ESI): M+H⁺=402.0; ¹H NMR (300MHz, CDCl₃) δ 7.71 (s, 1H), 6.22 (s, 1H), 4.30 (s, 2H), 4.08-4.04 (m,1H), 3.16-3.09 (m, 1H), 2.39 (s, 3H), 2.30-2.22 (m, 1H), 1.28-1.07 (m,1H), 1.05-1.03 (m, 2H).

Example 28:7-[[5-Chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-N-ethyl-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide

Step 1: Ethyl 3-bromo-2-oxobutanoate

Into each of two 3000-mL 3-necked round-bottom flasks purged andmaintained with an inert atmosphere of nitrogen was placeddichloromethane (1500 mL) and ethyl 2-oxobutanoate (286 g, 2.20 mol,1.00 equiv) followed by the addition of dibromane (352 g, 2.20 mol, 1.00equiv) dropwise with stirring at 0-5° C. The resulting solutions werestirred at 25° C. overnight. The combined reactions were quenched by theaddition of 3000 mL of saturated aqueous sodium bicarbonate. Theresulting solution was extracted with 2×500 mL of dichloromethane andthe combined organic layers were dried over anhydrous Na₂SO₄ andconcentrated under vacuum to afford 780 g (85%) of ethyl3-bromo-2-oxobutanoate as yellow oil.

Step 2: Ethyl 2-amino-5-methylthiazole-4-carboxylate hydrobromide

Into each of three 3000-mL round-bottom flasks was placed ethanol (2100mL), thiourea (101.5 g, 1.33 mol, 1.03 equiv), and ethyl3-bromo-2-oxobutanoate (270 g, 1.29 mol, 1.00 equiv). The resultingsolutions were stirred at 85° C. in an oil bath overnight. The combinedreaction mixtures were cooled to room temperature and filtered to afford840 g (crude) of ethyl 2-amino-5-methylthiazole-4-carboxylatehydrobromide as a light yellow solid.

Step 3: 2-Amino-N-ethyl-5-methyl-1,3-thiazole-4-carboxamide

Into a 50000-mL pressure tank reactor was placed a solution ofethanamine in ethanol (3500 mL) and ethyl2-amino-5-methylthiazole-4-carboxylate hydrobromide (400 g, 2.15 mol,1.00 equiv). The resulting solution was stirred at 120° C. for 64 h.This reaction was repeated once. The combined resulting mixtures wereconcentrated under vacuum. The residue was applied onto a silica gelcolumn eluting with dichloromethane/methanol (20:1) to afford 300 g(38%) of 2-amino-N-ethyl-5-methyl-1,3-thiazole-4-carboxamide as a yellowsolid.

Step 4:7-(Chloromethyl)-N-ethyl-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide

Into each of two 3000-mL 3-necked round-bottom flasks was placed PPA(1500 g), ethyl 4-chloro-3-oxobutanoate (603 g, 3.66 mol, 4.50 equiv),and 2-amino-N-ethyl-5-methyl-1,3-thiazole-4-carboxamide (150 g, 809.73mmol, 1.00 equiv). The resulting solutions were stirred at 110° C. for 2h. The combined reaction mixtures were cooled to 80° C. and quenchedcarefully by the addition of 450 mL of water. The pH of the solution wasadjusted to 8 with saturated aqueous sodium carbonate. The solids werecollected by filtration and washed with DCM to afford 260 g (56%) of7-(chloromethyl)-N-ethyl-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamideas a yellow solid.

Step 5:7-[[5-Chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-N-ethyl-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide

Into each of two 3000-mL round-bottom flasks purged and maintained withan inert atmosphere of nitrogen was placed CH₃CN (1500 mL), potassiumcarbonate (126 g, 911.66 mmol, 2.00 equiv), KI (38 g, 0.50 equiv),5-chloro-3-(trifluoromethyl)-1H-pyrazole (160 g, 938.31 mmol, 2.00equiv), and7-(chloromethyl)-N-ethyl-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(130 g, 454.94 mmol, 1.00 equiv). The resulting solutions were stirredat 80° C. for 4 h. The combined reaction mixtures were cooled to roomtemperature, concentrated under vacuum, and dissolved in 8 L of ethylacetate. The solids were filtered out. The resulting filtrate wasconcentrated under vacuum. The crude product was re-crystallized fromEtOAc. The residue was applied onto a silica gel column eluted withpetroleum ether/EtOAc/DCM (1:1:1). The crude product was purified byHPLC (Column: SO230330-2, C18, 330 g, 20-45 um, 100 A; 254 nm, 220 nm;CH₃CN: 0.05% TFA/H₂O=40%-65%, 20 min) to give 50 g (13%) of7-[[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-N-ethyl-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamideas a white solid. LCMS (ESI): M+H⁻=420; ¹H NMR (300 MHz, CDCl₃) δ 6.58(s, 1H), 5.93 (s, 1H), 5.72 (s, 1H), 3.47-3.56 (m, 2H), 2.42 (s, 3H),1.25-1.30 (t, J=7.2 Hz, 3H).

Example 39:3-[[3-(2,2-Difluorocyclopropyl)-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl]methyl]-2-fluoro-benzonitrile

Step 1:3-((3-Bromo-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)-2-fluorobenzonitrile

To a solution of3-bromo-7-(chloromethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (500mg, 1.70 mmol) in 1,4-dioxane/water (10 mL/1 mL) in a sealed tube wasadded (3-cyano-2-fluorophenyl)boronic acid (420 mg, 2.55 mmol),bis(diphenylphosphino)ferrocene]palladium(II) dichloride (125 mg, 0.17mmol), and sodium carbonate (370 mg, 3.49 mmol). The resulting solutionwas stirred for 12 h at 80° C., and then concentrated in vacuo. Theresidue was purified by flash chromatography on silica gel eluting withdichloromethane/ethyl acetate (80/1) to afford3-((3-bromo-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)-2-fluorobenzonitrile(150 mg, 23%) as a light yellow solid. LCMS (ESI): [M+H]=378.0.

Step 2:3-([3-Ethenyl-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-7-yl]methyl)-2-fluorobenzonitrile

To a solution of 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (244mg, 1.58 mmol) in 1,4-dioxane/water (1.5 mL/0.5 mL) was added3-([3-bromo-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-7-yl]methyl)-2-fluorobenzonitrile(300 mg, 0.79 mmol), sodium carbonate (168 mg, 1.59 mmol), and1,1′-bis(diphenylphosphino)ferrocenepalladiumdichloride (50 mg, 0.07mmol). The resulting solution was stirred for 2 h at 90° C. The reactionwas quenched by water, then extracted with dichloromethane andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel eluting with dichloromethane/methanol (40/1) to afford of2-fluoro-3-([2-methyl-5-oxo-3-[2-(trifluoromethyl)cyclopropyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-7-yl]methyl)benzonitrile(178 mg, 69%) as a white solid. LCMS (ESI): M+H⁺=326.0.

Step 3:3-[[3-(2,2-Difluorocyclopropyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-7-yl]methyl]-2-fluorobenzonitrile

To a solution of3-([3-ethenyl-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-7-yl]methyl)-2-fluorobenzonitrile(80 mg, 0.25 mmol) in tetrahydrofuran (8 mL) was added sodium iodide (72mg, 0.48 mmol) and trimethyl(trifluoromethyl)silane (176 mg, 1.29 mmol).The resulting solution was stirred for 2 h at 65° C. The reaction wasquenched by water, then extracted with dichloromethane and concentratedin vacuo. The residue was purified by preparative HPLC (Column, XBridgePrep C₁₈ OBD Column, 5 um, 19×150 mm; mobile phase, water with 10 mmolmonosodium hydrogen carbonate and acetonitrile (24.0% acetonitrile up to46.0% in 10 min); Detector, UV 254/220 nm) to afford3-[[3-(2,2-difluorocyclopropyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-7-yl]methyl]-2-fluorobenzonitrileas a white solid (15.4 mg, 17%). LCMS (ESI): M+H⁺=376.0; ¹H NMR (300MHz, CDCl₃) δ 7.61-7.53 (m, 2H), 7.26-7.20 (m, 1H), 5.99 (s, 1H), 3.93(s, 2H), 2.80-2.74 (m, 1H), 2.40 (s, 3H), 1.98-1.84 (m, 1H), 1.60-1.46(m, 1H).

Example 47:7-[[2-Fluoro-3-(trifluoromethyl)phenyl]methyl]-3-(1H-imidazol-2-yl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-onehydrate)

Step 1: Methyl7-(chloromethyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxylate

To a solution of methyl 2-amino-5-methylthiazole-4-carboxylate (5 g,26.8 mmol) in PPA (30 mL) was added ethyl 4-chloro-3-oxobutanoate (8.82g, 53.6 mmol), and stirred for 1 h at 110° C. The mixture was quenchedby water, and the pH value of the solution was adjusted to 7 with sodiumhydroxide (1 mol/L). The resulting solution was extracted withdichloromethane and concentrated in vacuo. The residue was purified byflash chromatography on silica gel eluting with dichloromethane/ethylacetate (10/1) to afford methyl7-(chloromethyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxylate(3.2 g, 45%) as a yellow solid. LCMS (ESI): M+H⁺=273.0.

Step 2: Methyl7-(2-fluoro-3-(trifluoromethyl)benzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxylate

To a solution of methyl7-(chloromethyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxylate(900 mg, 3.14 mmol) in 1,4-dioxane/water (10 mL/0.5 mL) was added2-fluoro-3-(trifluoromethyl)phenylboronic acid (982 mg, 4.72 mmol),bis(diphenylphosphino)ferrocene]palladium(II) dichloride (150 mg, 0.21mmol), and potassium carbonate (869 mg, 6.29 mmol). The resultingsolution was stirred for 14 h at 90° C. and then concentrated in vacuo.The residue was purified by flash chromatography on silica gel elutingwith ethyl acetate/petroleum ether (1/1) to afford methyl7-(2-fluoro-3-(trifluoromethyl)benzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxylate(800 mg, 62%) as a yellow solid. LCMS (ESI): M+H⁺=401.0.

Step 3:7-(2-Fluoro-3-(trifluoromethyl)benzyl)-3-(hydroxymethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of methyl7-(2-fluoro-3-(trifluoromethyl)benzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxylate(300 mg, 0.72 mmol) in dichloromethane (10 ml) was added DIBAL-H (2 mL,1 mol/L in toluene) at −78° C. The reaction solution was stirred for 2 hat room temperature, and then quenched by water. The resulting solutionwas extracted with dichloromethane and concentrated in vacuo. Theresidue was purified by flash chromatography on silica gel eluting withdichloromethane/ethyl acetate (2/1) to afford7-(2-fluoro-3-(trifluoromethyl)benzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbaldehyde(136 mg, 50%) as a white solid. LCMS (ESI): M+H⁺=373.0.

Step 4:7-(2-Fluoro-3-(trifluoromethyl)benzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbaldehyde

To a solution of7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-3-(hydroxymethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(50 mg, 0.13 mmol) in dichloromethane (5 mL) was added1,1-bis(acetyloxy)-3-oxo-3H-11{circumflex over( )}[5],2-benziodaoxol-1-yl acetate (85 mg, 0.20 mmol). The resultingsolution was stirred overnight at room temperature. After the reactionwas quenched with water, then extracted with dichloromethane andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel eluting with dichloromethane/methanol (40/1) to afford7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carbaldehyde(38 mg, 76%) as an off-white solid. LCMS (ESI): M+H⁺=326.0.

Step 5:7-[[2-Fluoro-3-(trifluoromethyl)phenyl]methyl]-3-(1H-imidazol-2-yl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-onehydrate

To a solution of7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carbaldehyde(38 mg, 0.10 mmol) in ethanol (2 mL) was added ammonia (0.2 mL, 5.71mmol) and oxalaldehyde (200 mg, 3.45 mmol). The resulting solution wasstirred overnight at room temperature. After the reaction was quenchedwith water, then extracted with dichloromethane and concentrated invacuo. The residue was purified by preparative HPLC (Column, XBridgePrep C₁₈ OBD Column, 5 um, 19×150 mm; mobile phase, water with 10 mmolmonosodium hydrogen carbonate and acetonitrile (24.0% acetonitrile up to46.0% in 10 min); Detector, UV 254/220 nm) to afford7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-3-(1H-imidazol-2-yl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onemonohydrate as an off-white solid (4.5 mg, 10%). LCMS [M+H]⁺ 371.0; ¹HNMR (300 MHz, CDCl₃) δ 10.82 (br, 1H), 7.56-7.48 (m, 2H), 7.25-7.17 (m,3H), 6.03 (s, 1H), 5.02 (br, 2H), 3.98 (s, 2H), 2.56 (s, 3H).

Example 91:N-Ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methoxy-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide

Step 1: 2-Amino-N-ethyl-5-methoxy-1,3-thiazole-4-carboxamide

To a solution of 2-amino-5-chloro-N-ethyl-1,3-thiazole-4-carboxamide(1.00 g, 4.86 mmol) in methanol (5 mL) was added sodium methoxide (1.05g, 19.4 mmol). The resulting solution was stirred for 2 h at 50° C. andthen quenched with water. The resulting solution was extracted withdichloromethane and concentrated in vacuo. The residue was purified byflash chromatography on silica gel eluting with dichloromethane/methanol(20/1) to afford of 2-amino-N-ethyl-5-methoxy-1,3-thiazole-4-carboxamide(300 mg, 31%) as an off-white solid. LCMS (ESI): M+H⁺=202.0.

Step 2:7-(Chloromethyl)-N-ethyl-2-methoxy-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

To a solution of 2-amino-N-ethyl-5-methoxy-1,3-thiazole-4-carboxamide(2.50 g, 12.4 mmol) in polyphosphoric acid (30 mL) was added ethyl4-chloro-3-oxobutanoate (4.09 g, 24.8 mmol). The resulting solution wasstirred for 3 h at 60° C. The reaction mixture was diluted with methanol(50 mL) and the pH value of the solution was adjusted to 7 withtriethylamine. The mixture was added water (200 mL), and the resultingsolution was extracted with dichloromethane and concentrated in vacuo.The residue was purified by flash chromatography on silica gel elutingwith dichloromethane/methanol (50/1) to afford7-(chloromethyl)-N-ethyl-2-methoxy-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(190 mg, 5%) as an off-white solid. LCMS (ESI): M+H⁺=302.0.

Step 3:N-Ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methoxy-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide

To a solution of7-(chloromethyl)-N-ethyl-2-methoxy-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(280 mg, 0.93 mmol) in 1,4-dioxane/water (1.5 mL/0.5 mL) was added[2-fluoro-3-(trifluoromethyl)phenyl]boronic acid (400 mg, 1.92 mmol),tricyclohexylphosphane (260 mg, 0.93 mmol), diacetoxypalladium (100 mg,0.45 mmol), and potassium phosphate (400 mg, 1.88 mmol). The resultingsolution was stirred overnight at 90° C. and then concentrated invacuo.The residue was purified by preparative HPLC with the followingconditions (1#-Pre-HPLC-005(Waters)): Column, SunFire Prep C₁₈ OBDColumn, 5 um, 19*150 mm; mobile phase, water with 10 mmol monosodiumhydrogen carbonate and acetonitrile (50.0% acetonitrile up to 82.0% in10 min, down to 50.0% in 2 min); Detector, UV 254/220 nm to affordN-ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methoxy-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(31.6 mg, 8%) as an off-white solid. LCMS (ESI): M+H⁺=430.1; ¹H NMR (400MHz, CD₃OD) δ 7.68-7.61 (m, 2H), 7.36-7.32 (m, 1H), 6.19 (s, 1H), 4.08(s, 5H), 3.41-3.32 (m, 2H), 1.25-1.21 (m, 3H).

Example 105:2-Cyano-N-ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide

Step 1: 2-Amino-N-ethylthiazole-4-carboxamide

A solution of ethyl 2-aminothiazole-4-carboxylate (11.5 g, 72.7 mmol) inethanamine/ethanol (100 mL, 30%) was stirred for 2 h at 110° C. in asealed tube, and the resulting solution was concentrated in vacuo toafford 2-amino-N-ethylthiazole-4-carboxamide (12.3 g, 99%). LCMS (ESI):M+H⁺=172.0.

Step 2: 2-Amino-5-chloro-N-ethylthiazole-4-carboxamide

To a solution of 2-amino-N-ethylthiazole-4-carboxamide (12.3 g, 71.8mmol) in N,N-dimethyformaide (100 ml) was added N-chlorosuccinimide(10.5 g, 79.0 mmol). The resulting solution was stirred overnight at 50°C. and concentrated in vacuo. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/ethyl acetate(8/1) to afford 2-amino-5-chloro-N-ethylthiazole-4-carboxamide (7.6 g,51%) as a brown solid. LCMS (ESI): M+H⁺=206.0.

Step 3:2-Chloro-7-(chloromethyl)-N-ethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

To a solution of 2-amino-5-chloro-N-ethylthiazole-4-carboxamide (12.4 g,60.3 mmol) in polyphosphoric acid (30 mL) was addedethyl-4-chloro-3-oxobutanoate (20 g, 121 mmol). The reaction mixture wasstirred for 1 h at 110° C. The reaction was quenched by water/ice, andthe pH of the solution was adjusted to 7 with sodium hydroxide (1mol/L). The resulting solution was extracted with dichloromethane andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel eluting with dichloromethane/methanol (50/1) to afford2-chloro-7-(chloromethyl)-N-ethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide(4.7 g, 25%) as a brown solid. LCMS (ESI): M+H⁺=305.0, 307.0.

Step 4:2-Chloro-N-ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide

To a solution of2-chloro-7-(chloromethyl)-N-ethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(100 mg, 0.33 mmol) in 1,4-dioxane/water (1.5 mL/0.5 mL) was added2-fluoro-3-(trifluoromethyl)phenyl]boronic acid (100 mg, 0.48 mmol),potassium carbonate (90 mg, 0.65 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (50 mg,0.07 mmol). The resulting solution was stirred overnight at 90° C. andthen concentrated in vacuo. The residue was purified by preparative HPLC(Column, XBridge Prep C₁₈ OBD Column, 5 um, 19×150 mm; mobile phase,water with 10 mmol monosodium hydrogen carbonate and acetonitrile (24.0%acetonitrile up to 46.0% in 10 min); Detector, UV 254/220 nm) to afford2-chloro-N-ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(13.4 mg, 9%) as a white solid. LCMS (ESI): M+H⁺=434.0; ¹H NMR (300 MHz,CDCl₃) δ 7.61-7.44 (m, 2H), 7.31-7.19 (m, 1H), 6.10 (s, 1H), 5.84 (br,1H), 3.96 (s, 2H), 3.59-3.50 (m, 2H), 1.32-1.20 (m, 3H).

Step 5: Methyl3-(ethylcarbamoyl)-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-2-carboxylate

To a solution of2-chloro-N-ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(500 mg, 1.15 mmol) in methanol (10 mL) was added triethylamine (233 mg,2.30 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride (85 mg, 0.12 mmol). The resulting solution was stirred for 6h at 50° C. under carbon monoxide atmosphere about 10 atm and thenconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel eluting with dichloromethane/methanol (20/1) to affordmethyl3-(ethylcarbamoyl)-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-2-carboxylate(350 mg, 66%) as a brown solid. LCMS (ESI): M+H⁺=458.0.

Step 6:3-(Ethylcarbamoyl)-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-2-carboxylicacid

To a solution of methyl3-(ethylcarbamoyl)-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-2-carboxylate(170 mg, 0.37 mmol) in tetrahydrofuran/water (6 mL/2 mL) was addedlithium hydroxide (110 mg, 4.59 mmol). The reaction mixture was stirredfor 1 h at room temperature. The pH of the solution was adjusted to 6with aqueous HCl solution (1 mol/L). The resulting solution wasextracted with dichloromethane and concentrated in vacuo to afford3-(ethylcarbamoyl)-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-2-carboxylicacid (110 mg, 67%) as a brown solid. LCMS (ESI): M−H⁻=442.0.

Step 7:3-N-Ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-2,3-dicarboxamide

To a solution of3-(ethylcarbamoyl)-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-2-carboxylicacid (300 mg, 0.68 mmol) in dichloromethane (5 mL) was addedtriethylamine (200 mg, 1.98 mmol) and chloro(propan-2-yloxy)methanone(166 mg, 1.35 mmol) at 0° C. The mixture was stirred for 20 min at roomtemperature, and then ammonium hydroxide (0.5 mL, 30%) was added. Theresulting solution was stirred for 2 h at room temperature and thenconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel eluting with dichloromethane/methanol (50/1) to afford3-N-ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-2,3-dicarboxamide(152 mg, 51%) as a brown solid. LCMS (ESI): M+H⁺=443.0.

Step 8:2-Cyano-N-ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide

To a solution of3-N-ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-2,3-dicarboxamide(152 mg) in dichloromethane (5 mL) was added triethylamine (0.5 mL) andtrifluoroacetic anhydride (0.2 mL, 0.93 mmol). The resulting solutionwas stirred for 30 min at room temperature and concentrated in vacuo.The residue was purified by preparative HPLC (Column, SunFire Prep C₁₈OBD Column, 5 um, 19*150 mm; mobile phase, Water with 10 mmol monosodiumhydrogen carbonate and acetonitrile (50.0% acetonitrile up to 82.0% in10 min, down to 50.0% in 2 min); Detector, UV 254/220 nm) to afford2-cyano-N-ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(7.4 mg, 5%) as an off-white solid. LCMS (ESI): M+H⁺=424.9; ¹H NMR (300MHz, CDCl₃) δ 7.61-7.54 (m, 1H), 7.50-7.46 (m, 1H), 7.26-7.21 (m, 1H),6.55 (br, 1H), 6.18 (s, 1H), 3.99 (s, 2H), 3.61-3.52 (m, 2H), 1.33-1.26(m, 3H).

Example 153:7-[(5-Cyclopropyltriazol-1-yl)methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one

Step 1: 7-(Azidomethyl)-3-bromo-2-methyl-thiazolo[3,2-a]pyrimidin-5-one

Sodium azide (134 mg, 2.04 mmol) in water (0.85 mL) was added to asolution of3-bromo-7-(chloromethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one (200mg, 0.68 mmol) in acetonitrile (3.4 mL, 0.2 M). The mixture was stirredat room temperature for 20 h and at 50° C. for another 20 h. Water (10mL) was added and the product was recovered by filtration. The solid waswashed with cold water and heptane and was dried under vacuum to afford7-(azidomethyl)-3-bromo-2-methyl-thiazolo[3,2-a]pyrimidin-5-one as abeige solid (167 mg, 82%). LCMS (ESI): M+H⁺=300.1, 302.1; ¹H NMR (400MHz, DMSO-d₆) δ 6.21 (d, J=0.8 Hz, 1H), 4.35 (s, 2H), 2.33 (s, 3H).

Step 2:3-Bromo-7-[(5-cyclopropyltriazol-1-yl)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one

A degassed solution ofchloro(pentamethylcyclopentadienyl)bis(triphenylphosphine)ruthenium(II)(12 mg, 0.01 mmol) in 1,4-dioxane (1.5 mL) with N₂ was added to asolution of7-(azidomethyl)-3-bromo-2-methyl-thiazolo[3,2-a]pyrimidin-5-one (89 mg,0.29 mmol) and ethynylcyclopropane (59 mg, 0.89 mmol) in 1,4-dioxane(1.5 mL) under N₂. The mixture was capped and stirred at 60° C. for 20h. The crude mixture was adsorbed on diatomaceous earth and purified byflash chromatography (0-5% MeOH/DCM gradient) to yield3-bromo-7-[(5-cyclopropyltriazol-1-yl)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-oneas a beige solid (90 mg, 83%). LCMS (ESI): M+H⁺=366.1, 368.1; ¹H NMR(400 MHz, Chloroform-d) δ 7.35 (s, 1H), 5.78 (s, 1H), 5.45 (s, 2H), 2.36(s, 3H), 1.71-1.65 (m, 1H), 1.07-0.97 (m, 2H), 0.76-0.67 (m, 2H).

Step 3:7-[(5-Cyclopropyltriazol-1-yl)methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one

Pd[dppf]Cl₂ (18 mg, 0.02 mmol) was added to a solution of3-bromo-7-[(5-cyclopropyltriazol-1-yl)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one(90 mg, 0.24 mmol), potassiumtrifluoro-[2-(hydroxymethyl)cyclopropyl]borane (65 mg, 0.37 mmol), andK₂CO₃ (68 mg, 0.49 mmol) in 1,4-dioxane/water (1.5 mL, 10:1) under N₂ ina microwave vessel. The vial was capped and heated at 120° C. for 45 minin the microwave. The crude reaction was filtered through a pad ofdiatomaceous earth and the filtrate was concentrated to dryness. Thecrude product was purified by flash chromatography (0-10% MeOH/DCMgradient) to give7-[(5-cyclopropyltriazol-1-yl)methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-oneas a white solid (16 mg, 18%). LCMS (ESI): M+H⁺=358.2; ¹H NMR (400 MHz,DMSO-d₆) δ 7.44 (s, 1H), 5.73 (s, 1H), 5.51 (s, 2H), 4.54 (t, J=5.5 Hz,1H), 3.46 (t, J=5.7 Hz, 2H), 2.37 (s, 3H), 2.06-1.95 (m, 1H), 1.93-1.82(m, 1H), 1.34-1.21 (m, 1H), 0.99-0.91 (m, 2H), 0.90-0.78 (m, 2H),0.71-0.60 (m, 2H).

Example 206:3-(Azetidin-1-yl)-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one

A mixture of3-bromo-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one(50 mg, 0.10 mmol), azetidine hydrochloride (12 mg, 0.12 mmol), andK₂CO₃ (36 mg, 0.26 mmol) in acetonitrile (0.5 mL) was stirred at 80° C.for 3 h and at room temperature for 20 h. The mixture was filtered toremove the salts and adsorbed on diatomaceous earth. The crude productwas purified by flash chromatography (10% EtOAc/heptane) followed by asecond purification by preparative HPLC to provide3-(azetidin-1-yl)-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-oneis a yellow lyophilized solid (11 mg, 24%). LCMS (ESI): M+H⁺=458.0; ¹HNMR (400 MHz, DMSO-d₆) δ 7.14 (s, 1H), 5.86 (s, 1H), 5.37 (s, 2H), 4.20(td, J=7.6, 7.1, 1.8 Hz, 4H), 2.24 (p, J=7.7 Hz, 2H).

Examples 207 and 208:2-(7-((5-Chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-(trifluoromethyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)cyclopropanecarbonitrile(Enantiomers)

Step 1: N,N-Dimethyl-3-(trifluoromethyl)-1H-pyrazole-1-sulfonamide

Into a 20-L 4-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen was placed 3-(trifluoromethyl)-1H-pyrazole(1000 g, 7.35 mol, 1.00 equiv), CH₃CN (10 L), and1,4-diazabicyclo[2.2.2]octane (990 g, 8.83 mol, 1.20 equiv) followed bythe addition of N,N-dimethylsulfamoyl chloride (1156 g, 8.05 mol, 1.10equiv) dropwise with stirring at 0° C. The resulting solution wasstirred at room temperature for 3 h, concentrated under vacuum, dilutedwith 10 L of H₂O, and extracted with 3×5 L of ethyl acetate. Thecombined organic layers were washed with 2×5 L of brine, dried overanhydrous sodium sulfate and concentrated under vacuum. The residue wasapplied onto a silica gel column eluted with dichloromethane to afford1700 g (95%) ofN,N-dimethyl-3-(trifluoromethyl)-1H-pyrazole-1-sulfonamide as colorlessoil.

Step 2:5-Chloro-N,N-dimethyl-3-(trifluoromethyl)-1H-pyrazole-1-sulfonamide

Into a 20-L 4-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen was placedN,N-dimethyl-3-(trifluoromethyl)-1H-pyrazole-1-sulfonamide (1200 g, 4.93mol, 1.00 equiv) and tetrahydrofuran (10 L) followed by the addition ofn-BuLi (2.5 M in hexane) (2.37 L, 1.20 equiv) dropwise with stirring at−78° C. The mixture was stirred at −70 to −80° C. for 1 h. To this wasadded a solution of C₂Cl₆ (1605 g, 1.40 equiv) in tetrahydrofuran (2.5L) dropwise with stirring at −70° C. The resulting solution was stirredat −70° C. for 3 h, quenched by the addition of 1000 mL of saturatedaqueous NH₄Cl, and extracted with 2×1 L of ethyl acetate. The combinedorganic layers were washed with 2×3 L of brine, dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column eluted with ethyl acetate/petroleum ether(1:30) to afford 1120 g (82%) of5-chloro-N,N-dimethyl-3-(trifluoromethyl)-1H-pyrazole-1-sulfonamide aslight yellow oil.

Step 3: 5-Chloro-3-(trifluoromethyl)-1H-pyrazole

Into a 10-L 4-necked round-bottom flask was placed5-chloro-N,N-dimethyl-3-(trifluoromethyl)-1H-pyrazole-1-sulfonamide(2200 g, 7.92 mol, 1.00 equiv) and dichloromethane (2000 mL) followed bythe addition of trifluoroacetic acid (1500 mL, 3.00 equiv) dropwise withstirring at 0° C. The resulting solution was stirred at room temperaturefor 5 h, concentrated under vacuum, and diluted with 6 L of H₂O. The pHof the solution was adjusted to 8-9 with sodium bicarbonate. Theresulting solution was extracted with 3×4 L of ethyl acetate. Thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated under vacuum. The crude product was purified bydistillation under reduced pressure (15 mm Hg) and the fraction wascollected at 52-65° C. The crude product was re-crystallized fromDCM/n-hexane (1:50) to afford 520 g (38%) of5-chloro-3-(trifluoromethyl)-1H-pyrazole as a white solid. LCMS (ESI):M+H⁺=171.

Step 4:2-(Tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropane-1-carbonitrile

Into a 30-mL sealed tube purged and maintained with an inert atmosphereof nitrogen a solution of cyclopropanecarbonitrile (1.0 g, 14.9 mmol) intetrahydrofuran (12.2 mL) was added [Ir(COD)OMe]₂ (320 mg, 0.25 mmol),bis(pinacolato) diboron (1.59 g, 12.5 mmol) and2,9-dimethylphenanthroline (50.5 mg, 0.49 mmol). The reaction mixturewas stirred at 90° C. for 18 h and concentrated in vacuo. The residuewas purified by chromatography with ethyl acetate/petroleum ether (1:4)to afford2-(tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropane-1-carbonitrile as alight yellow oil (1 g, crude).

Step 5: Potassium 2-(cyano)cyclopropyltrifluoroborate

To a solution of2-(tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropane-1-carbonitrile (180g, crude) in methanol (4.5 L) was added difluorane potassium (9.98 g,129 mmol) in H₂O (2 L). The resulting reaction mixture stirred at roomtemperature for 12 h and concentrated in vacuo. The residue was washedwith propan-2-one (6×1.5 L). The filtrate was concentrated in vacuo,dissolved with water (5 L), and washed with DCM (3×3 L) and EtOAc (3×3L). The water layer was freeze-dry to afford2-(trifluoro-lambda4-boranyl)cyclopropane-1-carbonitrile potassium as awhite solid (151.9 g, about 30% in two steps).

Step 6: 5-Bromo-1,3-thiazol-2-amine

To a mixture of sodium bicarbonate (5.8 kg, 69.04 mol, 3.00 equiv) inwater (30 L) and dichloromethane (20 L) was added5-bromo-1,3-thiazol-2-amine hydrobromide (6 kg, 23.08 mol, 1.00 equiv)in batches. The resulting mixture was stirred at room temperature for 4h and extracted with dichloromethane. The combined organic layers weredried over anhydrous sodium sulfate and concentrated under vacuum toafford 5-bromo-1,3-thiazol-2-amine as a gray solid (2.9 kg, 70%).

Step 7: 5-Bromo-2-chloro-1,3-thiazole

To a solution of 5-bromo-1,3-thiazol-2-amine (1 kg, 5.59 mol, 1.00equiv) in CH₃CN (7 L) was added CuCl (0.83 kg, 8.4 mol, 1.5 equiv)followed by the addition of t-BuONO (1.15 kg, 11.2 mol, 2.00 equiv)dropwise with stirring. The reaction mixture was stirred at 70° C.overnight, cooled to room temperature, quenched with water, andextracted with dichloromethane. The combined organic layers were driedover anhydrous sodium sulfate and concentrated. The residue was purifiedby chromatography eluted with diethyl ether/petroleum ether (1/20) toafford 5-bromo-2-chloro-1,3-thiazole as a yellow solid (0.4 kg, 36%).

Step 8: 4-Bromo-2-chloro-5-iodo-1,3-thiazole

To a solution of 5-bromo-2-chloro-1,3-thiazole (500 g, 2.52 mol, 1.00equiv) in tetrahydrofuran (8 L) was added LDA (1517 mL, 2 mol/L, 3 mmol,1.20 equiv) dropwise with stirring at −70° C. under nitrogen atmosphere.The resulting solution was stirred at −70° C. for 2 h. To this reactionmixture was added a solution of I₂ (967 g, 3.81 mol, 1.50 equiv) intetrahydrofuran (3 L) dropwise with stirring at −70° C. The reactionmixture was stirred at room temperature overnight, quenched with water,and extracted with dichloromethane. The combined organic layers weredried over anhydrous sodium sulfate and concentrated under vacuum togive a residue, which was purified by chromatography eluted with ethylacetate/petroleum ether (1:50) to afford4-bromo-2-chloro-5-iodo-1,3-thiazole (500 g, 61%) as a gray solid.

Step 9: 4-Bromo-2-chloro-5-(trifluoromethyl)-1,3-thiazole

To a mixture of 4-bromo-2-chloro-5-iodo-1,3-thiazole (500 g, 1.54 mol,1.00 equiv) in N,N-dimethylformamide (5 L) was added CuI (440 g, 2.31mol, 1.50 equiv) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (593g, 3.09 mol, 2.00 equiv). The reaction mixture was stirred at 80° C.overnight under nitrogen atmosphere, cooled to room temperature, andfiltered. The filtrate was diluted with water and extracted with ether.The combined organic layers were washed with brine, dried over anhydroussodium sulfate and concentrated under vacuum to give a residue, whichwas purified by chromatography eluting with diethyl ether/petroleumether (1/20) to afford 4-bromo-2-chloro-5-(trifluoromethyl)-1,3-thiazoleas a light yellow oil (300 g, crude), which was used in next stepwithout further purification.

Step 10: 4-Bromo-5-(trifluoromethyl)-1,3-thiazol-2-amine

To a solution of 4-bromo-2-chloro-5-(trifluoromethyl)-1,3-thiazole (300g, 1.13 mol, 1.00 equiv) in 1,4-dioxane (2 L) was added NH₃/H₂O (28%, 2L). The resulting solution was stirred at 50° C. overnight. Theresulting solution was extracted with ethyl acetate. The combinedorganic layers were dried over anhydrous sodium sulfate and concentratedunder vacuum to give a residue, which was purified by chromatographyeluted with ethyl acetate/petroleum ether (1:8) to afford4-bromo-5-(trifluoromethyl)-1,3-thiazol-2-amine as a light yellow solid(160 g, 42% in 2 steps).

Step 11:3-Bromo-7-(chloromethyl)-2-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a mixture of 4-bromo-5-(trifluoromethyl)-1,3-thiazol-2-amine (320 g,1.30 mol, 1.00 equiv) in PPA (3200 g) was added ethyl4-chloro-3-oxobutanoate (1068 g, 6.49 mol, 5.00 equiv). The resultingmixture was stirred at 130° C. for 2 h, quenched by the addition ofwater, and extracted with ethyl acetate. The combined organic layerswere dried over anhydrous sodium sulfate and concentrated under vacuumto give a residue, which was purified by chromatography eluted withethyl acetate/petroleum ether (1/10) to afford3-bromo-7-(chloromethyl)-2-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas a light yellow solid (306 g, 68%). LCMS (ESI): M+H⁺=348.9.

Step 12:3-Bromo-7-((5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-(trifluoromethyl)-5H-thiazolo[3,2-a]pyrimidin-5-one

To a mixture of3-bromo-7-(chloromethyl)-2-(trifluoromethyl)-5H-thiazolo[3,2-a]pyrimidin-5-one(1 g, 2.88 mmol) in acetonitrile (10 mL) was added sodium carbonate (610mg, 5.75 mmol) and 5-chloro-3-(trifluoromethyl)-1H-pyrazole (590 mg,3.45 mmol). The resulting mixture was stirred overnight at 80° C. After30 iterations on the same scale, the mixtures were combined, thenfiltered and concentrated in vacuo. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(1:20) to afford3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-(trifluoromethyl)-5H-thiazolo[3,2-a]pyrimidin-5-one(13.5 g, 40%) as a light yellow solid and3-bromo-7-((3-chloro-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-(trifluoromethyl)-5H-thiazolo[3,2-a]pyrimidin-5-one(6.0 g, 15%) a light yellow solid. LCMS (ESI): M+H⁺=480.9.

Step 13:2-(7-[[5-Chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)cyclopropane-1-carbonitrile(Cis Enantiomers)

To a mixture of3-bromo-7-[[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(500 mg, 1.03 mmol) in 1,4-dioxane/water (10 mL/1 mL) was added[bis(diphenylphosphino)ferrocene]palladium(II) dichloride (171 mg, 0.23mmol), sodium carbonate (500 mg, 4.68 mmol), and2-(trifluoro-lambda4-boranyl)cyclopropane-1-carbonitrile potassium (500mg, 2.87 mmol). The resulting mixture was stirred overnight at 85° C.The reaction was repeated 20 times on the same scale and combined. Theresulting mixture was extracted with dichloromethane and concentrated invacuo. The residue was purified by flash chromatography on silica geleluting with ethyl acetate/petroleum ether (1/2) to afford the racemicproduct (4.5 g, 46%). Then the racemic product was separated withsupercritical fluid chromatography (Column: Phenomenex Lux 5uCellulose-4,250*50 mm; Mobile Phase: CO₂:MeOH=50:50; Flow rate: 160mL/min; detector: 220 nm) to afford two enantiomers. Enantiomer 1 (Peak1, 1.88 g, 20%, white solid): Retention Time: 4.43 min; LCMS (ESI):M+H⁺=468.0; ¹H NMR (400 MHz, CDCl₃) δ 6.60 (s, 1H), 5.81 (s, 1H), 5.27(s, 2H), 3.11-3.00 (m, 1H), 1.91-1.80 (m, 2H), 1.65-1.62 (m, 1H). Peak 2(Enantiomer 2, 1.89 g, 20%, white solid): Retention Time: 5.59 min; LCMS(ESI): M+H⁺=468.0; ¹H NMR (400 MHz, CDCl₃) δ 6.63 (s, 1H), 5.84 (s, 1H),5.29 (s, 2H), 3.15-3.07 (m, 1H), 1.95-1.86 (m, 2H), 1.68-1.59 (m, 1H).

Example 220:2-[7-[(N-Ethyl-4-fluoro-anilino)methyl]-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-1-(hydroxymethyl)cyclopropanecarbonitrile

Step 1: 7-(Chloromethyl)-3-(hydroxymethyl)thiazolo[3,2-a]pyrimidin-5-one

To methyl 7-(chloromethyl)-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxylate(0.2 g, 0.77 mmol) in 4 mL methanol at rt was added sodium borohydride(0.11 g, 2.9 mmol) over 1 min resulting in exotherm. After 5 min,additional NaBH₄ (50 mg) was added, resulting in gas evolution. After 1h, the mixture was partitioned between CH₂Cl₂ and 1 N HCl (aq). Thephases were separated and the aqueous phase was extracted with CH₂Cl₂.The combined organic phases were dried with Na₂SO₄ and concentrated ontosilica gel for purification using CombiFlash® (12 g column, 0 to 80%EtOAc in CH₂Cl₂, 15 min) to afford 36 mg (20%) of7-(chloromethyl)-3-(hydroxymethyl)thiazolo[3,2-a]pyrimidin-5-one as atan solid.

Step 2: 7-(Chloromethyl)-5-oxo-thiazolo[3,2-a]pyrimidine-3-carbaldehyde

To 7-(chloromethyl)-3-(hydroxymethyl)thiazolo[3,2-a]pyrimidin-5-one (36mg, 0.16 mmol) in 5 mL CH₂Cl₂ was added alumina (0.34 g, 3.3 mmol), thenpyridinium chlorochromate (0.17 g, 0.78 mmol). The mixture was stirredovernight, then filtered through diatomaceous earth and concentratedonto silica gel for purification using CombiFlash® (4 g column, 0 to 80%EtOAc in CH₂Cl₂, 15 min) to afford 28 mg (78%) of7-(chloromethyl)-5-oxo-thiazolo[3,2-a]pyrimidine-3-carbaldehyde as acolorless solid.

Step 3:(E)-3-[7-(Chloromethyl)-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-2-cyano-prop-2-enoate

To a solution of7-(chloromethyl)-5-oxo-thiazolo[3,2-a]pyrimidine-3-carbaldehyde (80 mg,0.35 mmol) and ethyl cyanoacetate (40 mg, 0.35 mmol) in 5 mL CH₂Cl₂ wasadded 1 drop of piperidine resulting in a bright yellow color. After 2h, the mixture was concentrated onto silica gel for purification usingCombiFlash® (4 g column, 0 to 40% EtOAc in CH₂Cl₂, 15 min) to afford 66mg (58%) of ethyl(E)-3-[7-(chloromethyl)-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-2-cyano-prop-2-enoateas a yellow solid.

Step 4: Ethyl2-[7-(chloromethyl)-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-1-cyano-cyclopropanecarboxylate

To a solution of trimethylsulfoxonium iodide (69 mg, 0.31 mmol) in 1 mLDMSO at rt was added sodium hydride (60% dispersion in paraffin liquid,12 mg, 0.31 mmol). The mixture was stirred 5 min at which time ethyl(E)-3-[7-(chloromethyl)-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-2-cyano-prop-2-enoate(66 mg, 0.20 mmol) in 1 mL DMSO was added quickly dropwise resulting ina dark orange color. The mixture was stirred 1 h, then partitionedbetween EtOAc and water. The phases were separated and the aqueous phaseextracted with EtOAc. The combined organic phases were washed withbrine, dried with Na₂SO₄, and concentrated onto silica for purificationusing CombiFlash® (12 g column, 0 to 80% EtOAc in CH₂Cl₂, 15 min) toafford 14 mg (20%) of ethyl2-[7-(chloromethyl)-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-1-cyano-cyclopropanecarboxylateas a single diastereomer.

Step 5:2-[7-(Chloromethyl)-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-1-(hydroxymethyl)cyclopropanecarbonitrile

To a solution of ethyl2-[7-(chloromethyl)-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-1-cyano-cyclopropanecarboxylate(14 mg, 0.04 mmol) in 2 mL MeOH at 0° C. was added sodium borohydride(22 mg, 0.58 mmol) in one portion. The mixture was warmed to roomtemperature and stirred overnight. The mixture was concentrated, thenpartitioned between CH₂Cl₂ and 1N HCl (aq). The phases were separated,and the aqueous phase extracted with CH₂Cl₂. The combined organic phaseswere dried with Na₂SO₄ and concentrated. The above process was repeated(3 mL MeOH and 40 mg NaBH₄ added at room temperature) to effect completeconversion. Workup as before and concentration onto silica gel forpurification using CombiFlash® (4 g column, 0 to 100% EtOAc in CH₂Cl₂,15 min) afforded 11 mg (90%) of2-[7-(chloromethyl)-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-1-(hydroxymethyl)cyclopropanecarbonitrileas a colorless solid.

Step 6:2-[7-[(N-Ethyl-4-fluoro-anilino)methyl]-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-1-(hydroxymethyl)cyclopropanecarbonitrile

A mixture of N-ethyl-4-fluoro-aniline (8 mg, 0.06 mmol) and2-[7-(chloromethyl)-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-1-(hydroxymethyl)cyclopropanecarbonitrile(11 mg, 0.04 mmol) in 2 mL acetonitrile was stirred for 3 d. The mixturewas concentrated onto silica for purification using CombiFlash® (4 gcolumn, 0 to 100% EtOAc in CH₂Cl₂, 15 min) to afford 7 mg (47%) of2-[7-[(N-ethyl-4-fluoro-anilino)methyl]-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-1-(hydroxymethyl)cyclopropanecarbonitrileas a colorless solid. ¹H NMR (400 MHz, Chloroform-d) δ 6.93 (m, 2H), 6.7(s, 1H), 6.61 (m, 2H), 6.25 (s, 1H), 4.33 (s, 2H), 4.16 (m, 2H), 3.48(m, 2H), 3.32 (d, J=11.2 Hz, 1H), 3.25 (ddd, J=8.5, 7.1, 1.5 Hz, 1H),1.76 (m, 1H), 1.55 (dd, J=8.3, 6.3 Hz, 1H), 1.24 (t, J=7.1 Hz, 3H). MSm/z 399.13 (M+H).

Example 222:7-[[5-Chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(2-hydroxy-1-methyl-ethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one

Step 1: Methyl 2-methyl-3-oxopentanoate

To a solution of methyl 3-oxopentanoate (10 g, 76.8 mmol) intetrahydrofuran (20 mL) was added potassium carbonate (21 g, 152 mmol)and iodomethane (12 g, 84.5 mmol). The resulting mixture was stirred for5 h at 70° C., and then cooled to room temperature. The mixture wasconcentrated in vacuo to afford methyl 2-methyl-3-oxopentanoate asyellow oil (12 g, crude).

Step 2: Methyl 4-bromo-2-methyl-3-oxopentanoate

To a solution of methyl 2-methyl-3-oxopentanoate (9.00 g, 62.4 mmol) inchloroform (25 mL, 310 mmol) was added Br₂ (12 g, 75.1 mmol). Theresulting solution was stirred for 12 h at 25° C., and then concentratedin vacuo to afford methyl 4-bromo-2-methyl-3-oxopentanoate (13 g, 93%)as yellow oil.

Step 3: Ethyl 2-(2-amino-5-methyl-1,3-thiazol-4-yl)propanoate

To a solution of methyl 4-bromo-2-methyl-3-oxopentanoate (10 g, 44.8mmol) in ethanol (100 mL, 1.72 mol) was added thiourea (4.8 g, 63.1mmol). The resulting solution was stirred for 12 h at 110° C. Thereaction mixture was cooled to room temperature and then concentrated invacuo. The residue was purified by flash chromatography on silica geleluting with ethyl acetate/petroleum ether (1/3) to afford ethyl2-(2-amino-5-methyl-1,3-thiazol-4-yl)propanoate (8 g, 83%) as a yellowoil. LCMS (ESI): M+H⁺=215.1.

Step 4: Ethyl2-[7-(chloromethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]propanoate

To a solution of ethyl 2-(2-amino-5-methyl-1,3-thiazol-4-yl)propanoate(10 g, 46.7 mmol) in polyphosphoric acid (54 g, 469 mmol) was addedethyl 4-chloro-3-oxobutanoate (6.6 g, 40.1 mmol). The resulting solutionwas stirred for 1 h at 110° C. and then cooled to room temperature. ThepH of the solution was adjusted to 7 with sodium carbonate (5%). Theresulting solution was extracted with ethyl acetate and concentrated invacuo. The residue was purified by flash chromatography on silica geleluting with ethyl acetate/petroleum ether (1/3) to afford ethyl2-[7-(chloromethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]propanoateas a brown solid (13 g, 88%). LCMS (ESI): M+H⁺=315.0.

Step 5:Ethyl2-(7-[[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-methyl-5-oxo-5H[1,3]thiazolo[3,2-a]pyrimidin-3-yl)propanoate

To a solution of ethyl2-[7-(chloromethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]propanoate(2 g, 6.35 mmol) in acetonitrile (30 mL) was added5-chloro-3-(trifluoromethyl)-1H-pyrazole (1.1 g, 6.45 mmol), potassiumiodide (1.06 g, 6.39 mmol), and potassium carbonate (2.2 g, 15.9 mmol).The resulting mixture was stirred for 2 h at 90° C., cooled to roomtemperature and concentrated in vacuo. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(1/4) to afford ethyl2-(7-[[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)propanoate(2.9 g, crude) as a brown solid. LCMS (ESI): M+H⁺=449.0.

Step 6:7-[[5-Chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-3-(1-hydroxypropan-2-yl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a solution of methyl2-(7-[[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)propanoate(60 mg, 0.14 mmol) in dichloromethane (6 mL) was added DIBAL-H (40 mg,0.28 mmol) at 0° C. The resulting solution was stirred for 12 h at 25°C., and the reaction was then quenched by water. The resulting solutionwas extracted with ethyl acetate and concentrated in vacuo. The residuewas purified by flash chromatography on silica gel eluting withdichloromethane/ethyl acetate (2/1) to afford7-[[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-3-(1-hydroxypropan-2-yl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(28.7 mg, 51%) as a light yellow oil. LCMS (ESI): M+H⁺=407.1; ¹H NMR(400 MHz, CDCl₃) δ 6.60 (s, 1H), 5.68 (s, 1H), 5.27 (s, 2H), 3.94-3.90(m, 2H), 2.43 (s, 3H), 1.74 (m, 1H), 1.38-1.37 (m, 3H).

Example 240:7-[[2-Fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-3-(1H-1,2,4-triazol-5-yl)thiazolo[3,2-a]pyrimidin-5-one

Step 1. Methyl7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxylate

Pd[dppf]Cl₂ (108 mg, 0.15 mmol) was added to a solution of methyl7-(chloromethyl)-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxylate(400 mg, 1.47 mmol), [2-fluoro-3-(trifluoromethyl)phenyl]boronic acid(457 mg, 2.20 mmol), and K₂CO₃ (405 mg, 2.93 mmol) in 1,4-dioxane/water(9 mL, 10:1) under N₂. The mixture was stirred at 90° C. for 20 h. Thereaction mixture was filtered through diatomaceous earth and washed withEtOAc. The crude product was adsorbed on diatomaceous earth and purifiedby flash chromatography (0-60% EtOAc/heptane gradient) to afford methyl7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxylateas an orange solid (409 mg, 70%). LCMS (ESI): M+H⁺=401.0; ¹H NMR (400MHz, DMSO-d₆) δ 7.70 (q, J=8.1 Hz, 2H), 7.38 (t, J=7.8 Hz, 1H), 6.18 (s,1H), 4.03 (s, 2H), 3.84 (s, 3H), 2.38 (s, 3H).

Step 2.7-[[2-Fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxylicacid

Methyl7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxylate(365 mg, 0.91 mmol) was dissolved in THF (9 mL) and LiOH 2 M (4.5 mL,9.12 mmol) was added. The mixture was stirred at 60° C. for 6 h. Themixture was extracted with DCM (3×20 mL). The aqueous layer wasacidified with 1 N HCl and extracted with DCM (4×20 mL). The organicswere dried with MgSO₄, filtered and concentrated to give7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo-[3,2-a]pyrimidine-3-carboxylicacid as a crude beige solid (186 mg, 53%). LCMS (ESI): M+H⁺=387.1.

Step 3.7-[[2-Fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide

Oxalyl chloride (42 μL, 0.47 mmol) was added to a solution of7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxylicacid (90 mg, 0.23 mmol,) and DMF (2 μL, 0.02 mmol) in DCM (1.5 mL) at 0°C. The mixture was stirred at room temperature for 30 min and then thereaction mixture was concentrated to dryness. The solvent was switchedfor THF (0.6 mL) and a solution of ammonia in 1,4-dioxane (0.5 mol/L, 4mL, 1.86 mmol) was added at 0° C. The mixture was stirred at roomtemperature for 30 min. The reaction was partitioned in water/DCM andextracted with DCM (3×10 mL). The organics were washed with brine, driedwith MgSO₄, filtered and concentrated to obtain7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamideas a crude pale yellow solid (73 mg, 81%). LCMS (ESI): M+H⁺=386.2.

Step 4.7-[[2-Fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-3-(1H-1,2,4-triazol-5-yl)thiazolo[3,2-a]pyrimidin-5-one

7-[[2-Fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide(73 mg, 0.19 mmol) in N,N-dimethylformamide dimethyl acetal (1.9 mL,14.2 mmol) was stirred at 100° C. for 4 h. The mixture was concentrated,treated with acetic acid (1.9 mL, 32.7 mmol) and hydrazine (120 μL, 3.78mmol), and stirred at 100° C. for 2 h. The reaction mixture wasconcentrated and purified by preparative HPLC and lyophilization toprovide7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-3-(1H-1,2,4-triazol-5-yl)thiazolo[3,2-a]pyrimidin-5-oneas a beige solid (19 mg, 25%). LCMS (ESI): M+H⁺=410.1; ¹H NMR (˜2:1triazole tautomer ratio, * denotes minor tautomer peaks, 400 MHz,DMSO-d₆) δ 14.19 (s, 1H), 8.52 (s, 1H), 7.79-7.65 (m, 2H), 7.39 (t,J=7.8 Hz, 1H), 6.13* (s, 0.3H), 6.04 (s, 0.7H), 4.02 (s, 2H), 2.33* (s,1H), 2.18 (s, 2H).

Example 244:3-Acetyl-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methoxy-thiazolo[3,2-a]pyrimidin-5-one

Step 1: 5-Methoxythiazol-2-amine

To a solution of 5-bromo-1,3-thiazol-2-amine hydrobromide (26 g, 100mmol) in methanol (100 mL) was added dropwise sodium methoxide (12 g,222 mmol) in 40 mL methanol at 0° C. The resulting solution was stirredfor 1 h at room temperature and the reaction was diluted with ethylacetate. The solids were filtered out and the filtrate was concentratedin vacuo to afford 5-methoxy-1,3-thiazol-2-amine (6.5 g, crude) as a tansolid. LCMS (ESI): M+H⁺=131.0.

Step 2: 2-(5-Methoxythiazol-2-yl)isoindoline-1,3-dione

To a solution of 5-methoxy-1,3-thiazol-2-amine (6.50 g, crude) inacetonitrile (100 mL) was added ethyl1,3-dioxo-2,3-dihydro-1H-isoindole-2-carboxylate (10.9 g, 49.9 mmol).The resulting solution was stirred overnight at 50° C. and thenconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel eluting with dichloromethane/petroleum ether (3/1) toafford 2-(5-methoxy-1,3-thiazol-2-yl)-2,3-dihydro-1H-isoindole-1,3-dione(5 g, 38%) as a light brown solid. LCMS (ESI): M+H⁺=261.0.

Step 3: 2-(4-Chloro-5-methoxythiazol-2-yl) isoindoline-1,3-dione

A solution of2-(5-methoxy-1,3-thiazol-2-yl)-2,3-dihydro-1H-isoindole-1,3-dione (4.00g, 15.4 mmol) in acetonitrile (100 mL) was treated withN-chlorosuccinimide (2.16 g, 16.2 mmol) and then stirred for 2 h at 90°C. The resulting mixture was concentrated in vacuo to afford2-(4-chloro-5-methoxy-1,3-thiazol-2-yl)-2,3-dihydro-1H-isoindole-1,3-dione(4.6 g, crude) as an orange solid. LCMS (ESI): M+H⁺=295.0.

Step 4: 4-Chloro-5-methoxythiazol-2-amine

To a solution of2-(4-chloro-5-methoxy-1,3-thiazol-2-yl)-2,3-dihydro-1H-isoindole-1,3-dione(4.6 g, 15.6 mmol) in methanol (50 mL) was added NH₂NH₂.H₂O (15 mL, 308mmol). The resulting solution was stirred for 4 h at room temperature.The solids were filtered out and the filtrate was concentrated in vacuoto afford 4-chloro-5-methoxy-1,3-thiazol-2-amine (2 g, 78%) as a lightbrown solid. LCMS (ESI): M+H⁺=165.0.

Step 5:3-Chloro-7-(chloromethyl)-2-methoxy-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of 4-chloro-5-methoxy-1,3-thiazol-2-amine (2.00 g, 12.1mmol) in PPA (30 g, 260 mmol) was added ethyl 4-chloro-3-oxobutanoate(6.00 g, 36.4 mmol). The resulting solution was stirred for 2 h at 60°C. and then quenched with water/ice. The resulting solution wasextracted with dichloromethane and concentrated in vacuo. The residuewas purified by flash chromatography on silica gel eluting with ethylacetate/petroleum ether (1/3) to afford3-chloro-7-(chloromethyl)-2-methoxy-5H-thiazolo[3,2-a]pyrimidin-5-one(1.5 g, 47%) as a light brown solid. LCMS (ESI): M+H⁺=265.0.

Step 6:3-Chloro-7-((5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methoxy-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-chloro-7-(chloromethyl)-2-methoxy-5H-thiazolo[3,2-a]pyrimidin-5-one(100 mg, 0.38 mmol) in acetonitrile (2 mL) was added5-chloro-3-(trifluoromethyl)-1H-pyrazole (78 mg, 0.46 mmol) andpotassium carbonate (104 mg, 0.75 mmol). The resulting solution wasstirred for 2 h at 80° C. and then concentrated in vacuo. The residuewas purified by preparative TLC with ethyl acetate/petroleum ether (1/2)to afford3-chloro-7-[[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-methoxy-5H-thiazolo[3,2-a]pyrimidin-5-one(24.4 mg, 16%) as a white solid. LCMS (ESI): M+H⁺=399.9; ¹H NMR (300MHz, CDCl₃) δ 6.58 (s, 1H), 5.73 (s, 1H), 5.23 (s, 2H), 4.02 (s, 3H).

Step 7:7-((5-Chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(1-ethoxyvinyl)-2-methoxy-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-chloro-7-[[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-methoxy-5H-thiazolo[3,2-a]pyrimidin-5-one(300 mg, 0.752 mmol) in 1,4-dioxane (8 mL) was addedtributyl(1-ethoxyethenyl)stannane (543 mg, 1.504 mmol), DIEA (194 mg,1.50 mmol), and bis(diphenylphosphino)ferrocene]palladium(II) dichloride(106 mg, 0.151 mmol). The resulting solution was stirred overnight at80° C. and then concentrated invacuo. The residue was purified bypreparative TLC with ethyl acetate/petroleum ether (1:2) to afford7-((5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(1-ethoxyvinyl)-2-methoxy-5H-thiazolo[3,2-a]pyrimidin-5-one(180 mg, 55%) as light yellow oil. LCMS (ESI): M+H⁺=435.0.

Step 8:3-Acetyl-7-((5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methoxy-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of7-((5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(1-ethoxyvinyl)-2-methoxy-5H-thiazolo[3,2-a]pyrimidin-5-one(180 mg, 0.414 mmol) in dichloromethane (10 mL) was added a solution ofhydrogen chloride in 1,4-dioxane (0.5 mL, saturated). The resultingsolution was stirred for 30 min at room temperature and thenconcentrated in vacuo. The residue was purified by preparative TLC withethyl acetate/petroleum ether (1/1) to afford3-acetyl-7-((5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methoxy-5H-thiazolo[3,2-a]pyrimidin-5-one(64.7 mg, 38%) as a white solid. LCMS (ESI): M+H⁺=407.0; ¹H NMR (300MHz, CDCl₃) δ 6.58 (s, 1H), 5.81 (s, 1H), 5.27 (s, 2H), 4.05 (s, 3H),2.50 (s, 3H).

Example 250:7-[[5-Chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-propanoyl-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one

Step 1: Methyl2-[[(tert-butoxy)carbonyl]amino]-1,3-thiazole-4-carboxylate

To a solution of 2-amino-1,3-thiazole-4-carboxylate (20 g, 126 mmol) and4-dimethylaminopyridine (1.54 g, 12.6 mmol) indichloromethane/tetrahydrofuran (200 mL/200 mL) was added di-tert-butyldicarbonate (33 g, 151 mmol). The resulting solution was stirred for 12h at room temperature and then concentrated in vacuo. The residue waspurified by chromatography with ethyl acetate/petroleum ether (1/2) toafford methyl2-[[(tert-butoxy)carbonyl]amino]-1,3-thiazole-4-carboxylate (28 g, 86%)as an off-white solid. LCMS (ESI): M+H⁺=259.0.

Step 2: 2-[[(tert-Butoxy)carbonyl]amino]-1,3-thiazole-4-carboxylic acid

To a solution of methyl2-[[(tert-butoxy)carbonyl]amino]-1,3-thiazole-4-carboxylate (28 g, 108mmol) in tetrahydrofuran (300 mL) was added a solution of lithiumhydroxide (10.4 g, 433 mmol) in water (150 mL). The resulting mixturewas stirred for 12 h at room temperature. The pH of the solution wasadjusted to 4 with hydrochloric acid (2 mol/L). The solids werecollected by filtration to afford2-[[(tert-butoxy)carbonyl]amino]-1,3-thiazole-4-carboxylic acid (20 g,76%) as an off-white solid. LCMS (ESI): M+H⁺=245.0.

Step 3: tert-ButylN-[4-[methoxy(methyl)carbamoyl]-1,3-thiazol-2-yl]carbamate

To a mixture of2-[[(tert-butoxy)carbonyl]amino]-1,3-thiazole-4-carboxylic acid (20.0 g,81.9 mmol) in dichloromethane (400 mL) was added methoxy(methyl)aminehydrochloride (16.0 g, 164 mmol), HATU (37.4 g, 98.3 mmol), andtriethylamine (16.6 g, 164 mmol). The resulting mixture was stirred for4 h at room temperature. The reaction was then quenched by water, thenextracted with ethyl acetate and concentrated in vacuo to affordtert-butyl N-[4-[methoxy(methyl)carbamoyl]-1,3-thiazol-2-yl]carbamate(20 g, 85%) as a light red solid. LCMS (ESI): M+H⁺=288.0.

Step 4: tert-Butyl N-(4-propanoyl-1,3-thiazol-2-yl)carbamate

To a solution of tert-butylN-[4-[methoxy(methyl)carbamoyl]-1,3-thiazol-2-yl]carbamate (5.00 g, 17.4mmol) in tetrahydrofuran (100 mL, 1.23 mol) was addedbromo(ethyl)magnesium (4.59 mL, 34.8 mmol) at −70° C. The resultingsolution was stirred for 12 h at room temperature. The reaction wasdiluted with saturated aqueous NH₄Cl (30 mL), extracted with ethylacetate, and concentrated in vacuo. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(1/3) to afford tert-butyl N-(4-propanoyl-1,3-thiazol-2-yl)carbamate(1.3 g, 29%) as a light yellow solid. LCMS (ESI): M+H⁺=257.0.

Step 5: 1-(2-Amino-1,3-thiazol-4-yl)propan-1-one

To a solution of tert-butyl N-(4-propanoyl-1,3-thiazol-2-yl)carbamate(1.3 g, 5.07 mmol) in dichloromethane (15 mL) was added trifluoroaceticacid (24 mL). The resulting solution was stirred for 2 h at 0° C. andthen concentrated in vacuo. The residue was dissolved in dichloromethaneand then washed with sodium bicarbonate (1 mol/L). The organic layerswere concentrated in vacuo to afford1-(2-amino-1,3-thiazol-4-yl)propan-1-one (750 mg, 90%) as a light yellowsolid. LCMS (ESI): M+H⁺=157.0.

Step 6: 1-(2-Amino-5-iodo-1,3-thiazol-4-yl)propan-1-one

To a solution of 1-(2-amino-1,3-thiazol-4-yl)propan-1-one (850 mg, 5.44mmol) in dichloromethane (20 mL) was added N-iodo-succinimide (1.35 g,5.99 mmol). The resulting mixture was stirred for 12 h at roomtemperature and then concentrated in vacuo. The residue was purified byflash chromatography on silica gel eluting with ethyl acetate/petroleumether (1/3) to afford 1-(2-amino-5-iodo-1,3-thiazol-4-yl)propan-1-one (1g, 65%) as a brown solid. LCMS (ESI): M+H⁺=283.0.

Step 7:2-(5-Iodo-4-propanoyl-1,3-thiazol-2-yl)-2,3-dihydro-1H-isoindole-1,3-dione

To a solution of 1-(2-amino-5-iodo-1,3-thiazol-4-yl)propan-1-one (500mg, 1.77 mmol) and triethylamine (89.7 mg, 0.89 mmol) in dichloromethane(30 mL) was added ethyl 1,3-dioxo-2,3-dihydro-1H-isoindole-2-carboxylate(777 mg, 3.54 mmol). The resulting mixture was stirred for 12 h at 40°C., and concentrated in vacuo. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(1/2) to afford2-(5-iodo-4-propanoyl-1,3-thiazol-2-yl)-2,3-dihydro-1H-isoindole-1,3-dione(450 mg, 62%) as a light red solid. LCMS (ESI): M+H⁺=413.0.

Step 8:2-(5-Iodo-4-propanoyl-1,3-thiazol-2-yl)-2,3-dihydro-1H-isoindole-1,3-dione

To a solution of2-(5-iodo-4-propanoyl-1,3-thiazol-2-yl)-2,3-dihydro-1H-isoindole-1,3-dione(450 mg, 1.09 mmol) in N,N-dimethylformamide (10 mL) was added ethyl2,2-difluoro-2-(fluorosulfonyl)acetate (450 mg, 2.18 mmol) and copper(I)iodide (416 mg, 2.18 mmol). The resulting mixture was stirred for 2 h at80° C. and then concentrated in vacuo. The residue was dissolved indichloromethane (20 mL), and the solids were filtered out. The resultingsolution was concentrated in vacuo to afford2-[4-propanoyl-5-(trifluoromethyl)-1,3-thiazol-2-yl]-2,3-dihydro-1H-isoindole-1,3-dione(230 mg, 59%) as a yellow solid. LCMS (ESI): M+H⁺=355.0.

Step 9: 1-[2-Amino-5-(trifluoromethyl)-1,3-thiazol-4-yl]propan-1-one

To a solution of2-[4-propanoyl-5-(trifluoromethyl)-1,3-thiazol-2-yl]-2,3-dihydro-1H-isoindole-1,3-dione(230 mg, 0.65 mmol) in acetonitrile (10 mL) was added hydrazinemonohydrate (0.31 mL, 6.38 mmol). The resulting solution was stirred for30 min at room temperature. After concentration, the residue waspurified by flash chromatography on silica gel eluting with ethylacetate/petroleum ether (1/1) to afford1-[2-amino-5-(trifluoromethyl)-1,3-thiazol-4-yl]propan-1-one (60 mg,41%) as a light yellow oil. LCMS (ESI): M+H⁺=225.0.

Step 10:7-(Chloromethyl)-3-propanoyl-2-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a mixture of1-[2-amino-5-(trifluoromethyl)-1,3-thiazol-4-yl]propan-1-one (60 mg,0.27 mmol) in polyphosphoric acid (1 g, 8.69 mmol) was added ethyl4-chloro-3-oxobutanoate (220 mg, 1.34 mmol). The resulting mixture wasstirred for 12 h at 130° C. The reaction was then quenched by water (25mL), extracted with ethyl acetate and concentrated in vacuo. The residuewas purified by flash chromatography on silica gel eluting with ethylacetate/petroleum ether (1/2) to afford7-(chloromethyl)-3-propanoyl-2-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(15 mg, 17%) as a yellow solid. LCMS (ESI): M+H⁺=325.0.

Step 11:7-[[5-Chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-3-propanoyl-2-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a mixture of7-(chloromethyl)-3-propanoyl-2-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(15 mg, 0.05 mmol) in acetonitrile (3 mL, 57.1 mmol) was added potassiumcarbonate (13 mg, 0.09 mmol) and5-chloro-3-(trifluoromethyl)-1H-pyrazole (10 mg, 0.06 mmol). Theresulting mixture was stirred for 2 h at 80° C. After filtration andconcentration, the residue was purified by chromatography with ethylacetate/petroleum ether (1/3) to afford7-[[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-3-propanoyl-2-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(4.5 mg, 21%) as a light brown solid. LCMS (ESI): M+H⁺=459.0; ¹H NMR(400 MHz, CDCl₃) δ 6.60 (s, 1H), 5.83 (s, 1H), 5.31 (s, 2H), 2.97-2.83(m, 2H), 1.29-1.25 (m, 3H).

Example 251:2-[7-[(3,5-Dichloropyrazol-1-yl)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile

Step 1: N,N-Dimethyl-1H-pyrazole-1-sulfonamide

A solution of 1H-pyrazole (30 g, 440 mmol) in tetrahydrofuran (500 mL)was treated with sodium hydride (26 g, 648 mmol, 60%) at 0° C., and thenstirred for 1 h at 0° C. N,N-Dimethylsulfamoyl chloride (95 g, 661 mmol)was added dropwise at 0° C. The resulting solution was stirred foradditional 2 h at room temperature and then quenched by water. Theresulting solution was extracted with dichloromethane and concentratedin vacuo. The residue was purified by flash chromatography on silica geleluting with ethyl acetate/petroleum ether (1/6) to afford toN,N-dimethyl-1H-pyrazole-1-sulfonamide (58 g, 75%) as colorless oil.LCMS (ESI): M+H⁺=175.0.

Step 2: 5-Chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide

To a solution of N,N-dimethyl-1H-pyrazole-1-sulfonamide (37.2 g, 212mmol) in tetrahydrofuran (600 mL) was added dropwise n-BuLi (127 mL, 2.5mmol/L) at −78° C. The resulting solution was stirred for 1 h at −78° C.Hexachloroethane (75.4 g, 318 mmol) in tetrahydrofuran (400 mL) wasadded dropwise at −78° C. The reaction mixture was allowed to warm toroom temperature and was stirred overnight at room temperature. Thereaction was then quenched by water, then extracted with dichloromethaneand concentrated in vacuo. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(1/6) to afford 5-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide as a redoil (39.5 g, 89%). LCMS (ESI): M+H⁺=209.0.

Step 3: 5-Chloro-1H-pyrazole

To a solution of 5-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide (30 g,143 mmol) in dichloromethane (500 mL) was added trifluoroacetic acid(45.7 g, 401 mmol). The reaction mixture was stirred for 2 h at roomtemperature and quenched by water. The pH of the solution was adjustedto 8 with saturated sodium bicarbonate. The resulting solution wasextracted with dichloromethane and concentrated in vacuo to afford5-chloro-1H-pyrazole as a reddish solid (14 g, 95%). LCMS (ESI):M+H⁺=103.0.

Step 4: 5-Chloro-1-nitro-1H-pyrazole

To a solution of 5-chloro-1H-pyrazole (14 g, 136 mmol) in aceticacid/acetic anhydride (36 mL/92 mL) was added fuming nitric acid (36mL). The resulting solution was stirred overnight at room temperature,and then diluted with water (500 mL). The solids were collected byfiltration to afford 5-chloro-1-nitro-1H-pyrazole as a yellow solid (7g, 35%).

Step 5: 5-Chloro-3-nitro-1H-pyrazole

A solution of 5-chloro-1-nitro-1H-pyrazole (3 g, 20.3 mmol) in anisole(53.6 mL) was stirred overnight at 130° C. The resulting solution wasdiluted with of H₂O:petroleum ether (1:1), then extracted with sodiumhydroxide (10%) and the aqueous layers combined. The pH of the solutionwas adjusted to 2 with hydrochloric acid (3 mol/L). The resultingsolution was extracted with ethyl acetate and concentrated in vacuo toafford 5-chloro-3-nitro-1H-pyrazole as a yellow solid (2.7 g, 90%).

Step 6:3-Bromo-7-[(5-chloro-3-nitro-1H-pyrazol-1-yl)methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-bromo-7-(chloromethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(400 mg, 1.36 mmol) in acetonitrile (50 mL) was added5-chloro-3-nitro-1H-pyrazole (211 mg, 1.43 mmol), KI (113 mg, 0.68mmol), and potassium carbonate (565 mg, 4.09 mmol). The resultingsolution was stirred for 2 h at 80° C., cooled, extracted withdichloromethane, and then concentrated in vacuo to afford3-bromo-7-[(5-chloro-3-nitro-1H-pyrazol-1-yl)methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas a gray solid (20 mg, 4%). LCMS (ESI): M+H⁺=405.0.

Step 7:7-((3-Amino-5-chloro-1H-pyrazol-1-yl)methyl)-3-bromo-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-bromo-7-((5-chloro-3-nitro-1H-pyrazol-1-yl)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(30 mg, 0.066 mmol) in ethanol/water (5 mL/1 mL) was added iron powder(29 mg, 0.52 mmol) and ammonium chloride (35 mg, 0.660 mmol). Thereaction mixture was stirred for 2 h at 80° C., cooled and extractedwith dichloromethane. The combined organic phase was concentrated invacuo to afford7-((3-amino-5-chloro-1H-pyrazol-1-yl)methyl)-3-bromo-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-oneas a gray solid (10 mg, 4%). LCMS (ESI): M+H⁺=375.0.

Step 8:3-Bromo-7-[(3,5-dichloro-1H-pyrazol-1-yl)methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a solution of7-[(5-amino-3-chloro-1H-pyrazol-1-yl)methyl]-3-bromo-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(1 g, 2.67 mmol) in acetonitrile (10 mL) was added tert-butyl nitrite(495 mg, 4.80 mmol) and copper(I) chloride (715 mg, 5.32 mmol). Theresulting mixture was stirred for 1 h at 25° C. and then concentrated invacuo. The residue was purified by flash chromatography on silica geleluting with ethyl acetate/petroleum ether (1/1) to afford3-bromo-7-[(3,5-dichloro-1H-pyrazol-1-yl)methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(200 mg, 19%) as a yellow solid. LCMS (ESI): M+H⁺=395.0.

Step 9:2-[7-[(3,5-Dichloro-1H-pyrazol-1-yl)methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropane-1-carbonitrile

To a solution of3-bromo-7-[(3,5-dichloro-1H-pyrazol-1-yl)methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(150 mg, 0.38 mmol) in acetonitrile/water (4 ml/0.4 ml) was added2-(trifluoro-lambda4-boranyl)cyclopropane-1-carbonitrile potassium (263mg, 1.52 mmol), sodium carbonate (80 mg, 0.75 mmol), and[bis(diphenylphosphino)ferrocene]palladium(II) dichloride (27 mg, 0.037mmol). The resulting solution was stirred for 14 h at 90° C. and thenconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel eluting with ethyl acetate/petroleum ether (1/1) to affordthe racemic product (45 mg, 31%). The racemic product was separated bychiral HPLC with the following conditions (Column: Chiralpak ic 0.46*25cm, 5 um; Mobile Phase: 100% MeOH-HPLC; Flow rate: 1 mL/min; detector:254 nm) to afford the title compound as a white solid (13.3 mg, 9%).Retention Time: 9.18 min; LCMS (ESI): M+H⁺=381.0; ¹H NMR (300 MHz,CDCl₃) δ 6.25 (s, 1H), 5.71 (s, 1H), 5.14 (s, 2H), 2.99-2.94 (m, 1H),2.39 (s, 3H), 1.84-1.79 (m, 1H), 1.69-1.66 (m, 1H), 1.45-1.35 (m 1H).

Example 258:7-[[5-Chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-(difluoromethyl)-N-ethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide

Step 1:2-Chloro-7-[[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-N-ethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide

To a solution of2-chloro-7-(chloromethyl)-N-ethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(2 g, 6.53 mmol) in acetonitrile (10 mL) was added5-chloro-3-(trifluoromethyl)-1H-pyrazole (872 mg, 5.11 mmol), potassiumiodide (542 mg, 3.26 mmol), and potassium carbonate (1.8 g, 13 mmol).The resulting mixture was stirred for 1 h at 80° C. and concentrated invacuo. The residue was purified by flash chromatography on silica geleluting with ethyl acetate/petroleum ether (1/1) to afford of2-chloro-7-[[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-N-ethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(1.1 g, 38%) as a yellow solid. LCMS (ESI): M+H⁺=441.0.

Step 2:7-[[5-Chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-ethenyl-N-ethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide

To a solution of2-chloro-7-[[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-N-ethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(500 mg, 1.14 mmol) in 1,4-dioxane/water (15 mL/1 mL) was added2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (349 mg, 2.27 mmol),sodium carbonate, (238 mg, 2.25 mmol) and[bis(diphenylphosphino)ferrocene]palladium(II) dichloride (83 mg, 0.11mmol). The resulting solution was stirred for 14 h at 90° C. and thenconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel eluting with ethyl acetate/petroleum ether (1/1) to afford7-[[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-ethenyl-N-ethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamideas a yellow solid (200 mg, 41%). LCMS (ESI): M+H⁺=432.0.

Step 3:7-[[5-Chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-N-ethyl-2-formyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide

To a solution of7-[[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-ethenyl-N-ethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(175 mg, 0.41 mmol) in 1,4-dioxane/water (5 mL/3 mL) was added osmiumtetraoxide (1.03 mg, 0.004 mmol), N-methylmorpholine-N-oxide (94.83 mg,0.811 mmol), and sodium periodate (173 mg, 0.81 mmol). The resultingsolution was stirred for 14 h at 25° C. and concentrated. The residuewas purified by flash chromatography on silica gel eluting with ethylacetate/petroleum ether (1/2) to afford7-[[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-N-ethyl-2-formyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(50 mg 28%) as a light yellow solid. LCMS (ESI): M+H⁺=456.0.

Step 4:7-((5-Chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-(difluoromethyl)-N-ethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide

To a solution of7-[[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-N-ethyl-2-formyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide(100 mg, 0.23 mmol) in dichloromethane (20 mL) was addedbis(2-methoxyethyl)amino]sulfur trifluoride (510 mg, 2.31 mmol) at 0° C.The resulting solution was stirred for 14 h at 25° C., and then quenchedby water. The resulting solution was extracted with ethyl acetate andconcentrated in vacuo to afford7-[[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-2-(difluoromethyl)-N-ethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamideas a white solid (21.2 mg, 20%). LCMS (ESI): M+H⁺=456.0; ¹H NMR (400MHz, CDCl₃) δ 7.10-6.83 (m, 1H), 6.59 (s, 1H), 6.37 (s, 1H), 5.80 (s,1H), 5.30 (s, 2H), 3.54-3.47 (m, 2H), 1.28-1.25 (m, 3H).

Examples 266 and 267:2-[2-Chloro-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile(Cis Enantiomers)

Step 1: tert-Butyl N-(4-bromo-5-chloro-1,3-thiazol-2-yl)carbamate

To a solution of tert-butyl N-(5-bromo-1,3-thiazol-2-yl)carbamate (5 g,17.9 mmol) in tetrahydrofuran (100 ml) was added dropwise LDA (29.4 ml,2 mol/L) at −78° C., and the resulting mixture was stirred for 1 h at−78° C. Then the mixture was added a solution of hexachloroethane (14 g,59.1 mmol) in tetrahydrofuran (50 ml) at −78° C. The reaction wasstirred for additional 15 h at room temperature. The reaction wasquenched by water, then extracted with dichloromethane and concentratedin vacuo. The residue was purified by flash chromatography on silica geleluting with ethyl acetate/petroleum ether (1/9) to afford tert-butylN-(4-bromo-5-chloro-1,3-thiazol-2-yl)carbamate (4.07 g, 72%) as brownoil. LCMS (ESI): M+H⁺=313.0.

Step 2: 4-Bromo-5-chloro-1,3-thiazol-2-amine

To a solution of tert-butylN-(4-bromo-5-chloro-1,3-thiazol-2-yl)carbamate (4.07 g, 13.0 mmol) indichloromethane (20 mL) was added trifluoroacetic acid (29.7 g, 260mmol), and the reaction was stirred for 15 h at room temperature. The pHof the solution was adjusted to 7 with saturated sodium bicarbonate,then extracted with dichloromethane and concentrated in vacuo. Theresidue was purified by flash chromatography on silica gel eluting withethyl acetate/petroleum ether (1/5) to afford4-bromo-5-chloro-1,3-thiazol-2-amine (1.02 g, 37%) as a brown solid.LCMS (ESI): M+H⁺=213.0.

Step 3:3-Bromo-2-chloro-7-(chloromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a solution of 4-bromo-5-chloro-1,3-thiazol-2-amine (700 mg, 3.28mmol) in polyphosphoric acid (2.81 g, 24.4 mmol) was added ethyl4-chloro-3-oxobutanoate (1.08 g, 6.56 mmol). The reaction mixture wasstirred for 1 h at 110° C. and cooled to room temperature. The reactionwas then quenched by water and the pH of the solution was adjusted to 7with sodium hydroxide (1 mol/L). The resulting solution was extractedwith dichloromethane and concentrated in vacuo. The residue was purifiedby flash chromatography on silica gel eluting with ethylacetate/petroleum ether (1/3) to afford3-bromo-2-chloro-7-(chloromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(900 mg, 87%) as a brown solid. LCMS (ESI): M+H⁺=313.0.

Step 4:3-Bromo-2-chloro-7-((5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-5H-thiazolo[3,2-a]pyrimidin-5-one

To a solution of3-bromo-2-chloro-7-(chloromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(500 mg, 1.59 mmol) in acetonitrile (10 mL) was added5-chloro-3-(trifluoromethyl)-1H-pyrazole (327 mg, 1.92 mmol), potassiumiodide (133 mg, 0.80 mmol), and potassium carbonate (442 mg, 3.20 mmol).The resulting solution was stirred for 2 h at 80° C. and cooled. Thesolid was filtered off and the filtrate was concentrated in vacuo. Theresidue was purified by flash chromatography on silica gel eluting withethyl acetate/petroleum ether (1/9) to afford3-bromo-2-chloro-7-(chloromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas a brown solid (300 mg, 60%). LCMS (ESI): M+H⁺=448.0.

Step 5:2-(2-Chloro-7-[[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)cyclopropane-1-carbonitrile(Enantiomer 1)

To a solution of3-bromo-2-chloro-7-[[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(100 mg, 0.22 mmol) in 1,4-dioxane/water (3 mL/0.3 mL) was addedpotassium 2-(cyano)cyclopropyltrifluoroborate (77.2 mg, 0.45 mmol),[bis(diphenylphosphino)ferrocene]palladium(II) dichloride (16.3 mg,0.022 mmol), and potassium phosphate (94.8 mg, 0.45 mmol). The resultingsolution was stirred for 14 h at 85° C. and concentrated in vacuo. Theresidue was purified by flash chromatography on silica gel eluting withethyl acetate/petroleum ether (1/1) to afford the racemic product (40mg, 41%). Then the racemic product was separated with chiral HPLC withthe following conditions (Column:Phenomenex Lux 5u Cellulose-4, AXIAPacked 250*21.2 mm, 5 um; Mobile Phase: 100% MeOH; Flow rate: 20 mL/min;detector: 254 nm/220 nm) to afford two enantiomers. Enantiomer 1 (Peak1, white solid, 7.5 mg, 8%): Retention Time: 1.54 min; LCMS (ESI):M+H⁺=434.0; ¹H NMR (400 MHz, CDCl₃) δ 6.59 (s, 1H), 5.74 (s, 1H), 5.24(s, 2H), 2.98-2.93 (m, 1H), 1.88-1.82 (m, 2H), 1.66-1.61 (m, 1H).Enantiomer 2 (Peak 2, 6.1 mg, 6%): Retention Time: 2.06 min; LCMS (ESI):M+H⁺=434.0; ¹H NMR (400 MHz, CDCl₃) δ 6.59 (s, 1H), 5.75 (s, 1H), 5.24(s, 2H), 2.99-2.89 (m, 1H), 1.88-1.82 (m, 2H), 1.66-1.61 (m, 1H).

The following examples were prepared using methods analogous to thosedescribed in the appropriate Reference Method or Example (Ref. Method orEx.) column. Satisfactory analytical data was obtained for eachcompound.

Ref. Method Ex. Structure/Name Chemical Name or Ex.  1

7-[(3-cyclopropyl-2-fluoro- phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Method 21  2

N-ethyl-2-methyl-5-oxo-7-[(2,3,6- trifluorophenyl)methyl]thiazolo[3,2-a]pyrimidine-3-carboxamide Method 21  3

2-fluoro-3-[(2-methyl-3-oxazol-2-yl-5- oxo-thiazolo[3,2-a]pyrimidin-7-yl)methyl]benzonitrile Method 24  4

7-[(5-cyano-3-cyclopropyl-2-fluoro- phenyl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Method 21  5

N-ethyl-7-[(2-fluoro-3-methoxy- phenyl)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Method 21  6

7-[(3-cyclopropyl-2-fluoro- phenyl)methyl]-6-fluoro-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Method 21  7

2-[7-[(3-chloro-2-fluoro- phenyl)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N- methyl-acetamide Method 2  8

7-[(3-chloro-2-fluoro-phenyl)methyl]- N-ethyl-6-fluoro-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Method 21  9

7-[(4,5-difluoro-2-methoxy- phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Method 21  10

2-fluoro-3-[[2-methyl-3-(2- methylcyclopropyl)-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl]methyl]benzonitrile Method 20  11

2-[7-[(3-cyclopropyl-2-fluoro- phenyl)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N- methyl-acetamide Method 2  13

N-ethyl-6-fluoro-7-[[2-fluoro-3- (trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidine-3-carboxamide Method 21  14

7-[[2-chloro-5- (trifluoromethyl)phenyl]methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2- a]pyrimidine-3-carboxamide Method 21  15

7-[(3-cyano-2-fluoro-phenyl)methyl]-6- fluoro-2-methyl-5-oxo-N-(2,2,2-trifluoroethyl)thiazolo[3,2- a]pyrimidine-3-carboxamide Method 21  16

7-[(2-chloro-4,5-difluoro- phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Method 21  17

7-[[4,5-difluoro-2-(2- fluoroethyl)phenyl]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidine-3-carboxamide Method 21  18

2-[7-[[5-cyclopropyl-3- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidin-3-yl]-N-methyl-acetamide Method2  19

2-[7-[[2-fluoro-3- (trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin- 3-yl]-N-methyl-acetamide Method 2 20

7-[(5-chloro-3-methyl-pyrazol-1- yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Ex. 28  21

7-[(3-chloro-5-methyl-pyrazol-1- yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Ex. 28  22

7-[(3-chloro-5-cyclopropyl-pyrazol-1- yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Ex. 28  23

7-[(5-chloro-3-cyclopropyl-pyrazol-1- yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Ex. 28  25

2-[7-[(N-ethyl-4-fluoro- anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N- methyl-acetamide Method 2  26

N-ethyl-2-methyl-7-[[5-methyl-3- (trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Ex. 28  27

N-ethyl-2-methyl-7-[[3-methyl-5- (trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Ex. 28  29

7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-2-methyl-5-oxo- thiazolo[3,2-a]pyrimidine-3-carboxamide Ex. 28  30

7-[[3-(difluoromethyl)-2-fluoro- phenyl]methyl]-6-fluoro-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Method 21  31

7-[[3-(difluoromethyl)-2-fluoro- phenyl]methyl]-N-ethyl-6-fluoro-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidine-3-carboxamide Method 21  32

7-(4-bicyclo[4.2.0]octa-1,3,5- trienylmethyl)-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Method 21  33

N-ethyl-7-[[2-fluoro-3-(1- hydroxycyclopropyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidine-3-carboxamide Method 21  34

6-fluoro-3-[2- (hydroxymethyl)cyclopropyl]-2-methyl- 7-[3-(trifluoromethyl)phenoxy]thiazolo[3,2- a]pyrimidin-5-one Ex. 12  35

N-ethyl-7-[[2-fluoro-3-(1- fluorocyclopropyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidine-3-carboxamide Method 21  36

N-ethyl-7-[[2-fluoro-3-[1- (fluoromethyl)vinyl]phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidine-3-carboxamide Method 21  37

7-[(2-ethynyl-4,5-difluoro- phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Method 21  38

2-fluoro-3-[[2-methyl-5-oxo-3-[2-(trifluoromethyl)cyclopropyl]thiazolo[3,2-a]pyrimidin-7-yl]methyl]benzonitrile Method 20  40

N-ethyl-7-[[2-fluoro-3- (trifluoromethyl)phenyl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidine-3-carboxamide Ex. 28  41

7-[(3-cyano-2-fluoro-phenyl)methyl]- N-ethyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidine-3-carboxamide Ex. 28  42

7-[[3-(difluoromethyl)-2-fluoro- phenyl]methyl]-N-ethyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidine-3-carboxamide Ex. 28  43

7-[[5-chloro-3-(trifluoromethyl)pyrazol- 1-yl]methyl]-N-ethyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidine-3-carboxamide Ex. 28  44

7-[[3-chloro-5-(trifluoromethyl)pyrazol- 1-yl]methyl]-N-ethyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidine-3-carboxamide Ex. 28  45

N-ethyl-7-[[5-methyl-3- (trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidine-3-carboxamide Ex. 28 46

N-ethyl-7-[[3-methyl-5- (trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[1,2- a]pyrimidine-3-carboxamide Ex. 28 48

N-ethyl-7-[2-fluoro-3- (trifluoromethyl)phenoxy]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Ex. 12  49

7-[(3-cyano-2-fluoro-5-methyl- phenyl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Method 21  50

7-[(3-chloro-2-fluoro-phenyl)methyl]- N-ethyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidine-3-carboxamide Ex. 28  51

7-[[2-fluoro-3- (trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-N-(2,2,2- trifluoroethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide Method 25  52

2-methyl-7-[[5-methyl-3- (trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-N-(2,2,2- trifluoroethyl)thiazolo[3,2- a]pyrimidine-3-carboxamideMethod 25  53

7-[[5-cyclopropyl-3- (trifluoromethyl)pyrazol-1-yl]methyl]-N-methyl-5-oxo-2- (trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide Ex. 28  54

7-[[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]methyl]-N-methyl-5-oxo-2- (trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide Ex. 28  55

7-[[5-chloro-3-(trifluoromethyl)pyrazol- 1-yl]methyl]-N-methyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidine-3-carboxamide Ex. 28  56

7-[[3-chloro-5-(trifluoromethyl)pyrazol- 1-yl]methyl]-N-methyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidine-3-carboxamide Ex. 28  57

7-[[5-cyclopropyl-3- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-N-(2,2,2- trifluoroethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide Method 25  58

7-[[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-N-(2,2,2- trifluoroethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide Method 25  59

7-[2-fluoro-3- (trifluoromethyl)phenoxy]-N,2-dimethyl-5-oxo-thiazolo[3,2- a]pyrimidine-3-carboxamide Ex. 12  60

2-chloro-N-ethyl-7-[[2-fluoro-3- (trifluoromethyl)phenyl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Ex. 258  61

N-methyl-7-[[5-methyl-3- (trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidine-3-carboxamide Ex. 28 62

N-methyl-7-[[3-methyl-5- (trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidine-3-carboxamide Ex. 28 63

7-[[2-fluoro-3- (trifluoromethyl)phenyl]methyl]-N- methyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidine-3-carboxamide Ex. 28  64

7-[(3-chloro-2-fluoro-phenyl)methyl]- N-methyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidine-3-carboxamide Ex. 28  65

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-N-(2,2,2- trifluoroethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide Method 25  66

7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-N-(2,2,2- trifluoroethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide Method 25  67

2-methyl-7-[[3-methyl-5- (trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-N-(2,2,2- trifluoroethyl)thiazolo[3,2- a]pyrimidine-3-carboxamideMethod 25  68

7-(3-cyano-2-fluoro-phenoxy)-N-ethyl- 2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide Ex. 12  69

2-chloro-7-[(3-cyano-2-fluoro- phenyl)methyl]-N-ethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Ex. 258  70

7-[(3-cyano-2-fluoro-phenyl)methyl]- N-methyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidine-3-carboxamide Ex. 28  71

N-ethyl-2-[7-[[2-fluoro-3- (trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin- 3-yl]acetamide Method 2  72

N,2-dimethyl-5-oxo-7-[[4- (trifluoromethyl)pyrazol-1-yl]methyl]thiazolo[3,2-a]pyrimidine-3- carboxamide Ex. 28  73

3-cyclopropyl-7-[2-fluoro-3- (trifluoromethyl)phenoxy]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one Ex. 12  74

3-[[2-chloro-5-oxo-3-[2- (trifluoromethyl)cyclopropyl]thiazolo[3,2-a]pyrimidin-7-yl]methyl]-2-fluoro- benzonitrile Ex. 267  75

2-[7-[[2-fluoro-3- (trifluoromethyl)phenyl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidin-3-yl]-N-methyl-acetamideMethod 2  76

7-[[5-cyclopropyl-3- (trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidine-3-carboxamide Ex. 28 77

2-fluoro-3-[2-methyl-5-oxo-3-[2-(trifluoromethyl)cyclopropyl]thiazolo[3,2-a]pyrimidin-7-yl]oxy-benzonitrile Ex. 12  78

2-[7-[[5-cyclopropyl-3- (trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-acetamide Method 2  79

2-[7-[[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-acetamide Method 2  80

7-[[2-fluoro-3- (trifluoromethyl)phenyl]methyl]-2- methyl-3-(methylsulfonylmethyl)thiazolo[3,2- a]pyrimidin-5-one Method 10  81

7-[[2-fluoro-3- (trifluoromethyl)phenyl]methyl]-3-(1H-imidazol-2-ylmethyl)-2-methyl- thiazolo[3,2-a]pyrimidin-5-one Method 10 82

N-ethyl-7-[(N-ethyl-4-fluoro- anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Ex. 28  83

N-ethyl-7-[(N-ethyl-4-fluoro- anilino)methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidine-3-carboxamide Ex. 28  84

2-fluoro-3-[[3-(2-methylcyclopropyl)-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-7-yl]methyl]benzonitrile Ex. 207  85

3-[[2-chloro-3-(2-methylcyclopropyl)- 5-oxo-thiazolo[3,2-a]pyrimidin-7-yl]methyl]-2-fluoro-benzonitrile Ex. 267  86

7-[2-fluoro-3- (trifluoromethyl)phenoxy]-2-methyl-3-(2-methylcyclopropyl)thiazolo[3,2- a]pyrimidin-5-one Ex. 12  87

N-ethyl-7-[[2-fluoro-3- (trifluoromethyl)phenyl]methyl]-2-isopropyl-5-oxo-thiazolo[3,2- a]pyrimidine-3-carboxamide Method 21  88

2-fluoro-3-[[5-oxo-2-(trifluoromethyl)- 3-[2-(trifluoromethyl)cyclopropyl]thiazolo[3,2-a]pyrimidin-7-yl]methyl]benzonitrile Ex. 207  89

6-[[5-chloro-3-(trifluoromethyl)pyrazol- 1-yl]methyl]-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4- a]pyrimidin-8-one Method 27  90

6-[[3-chloro-5-(trifluoromethyl)pyrazol- 1-yl]methyl]-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4- a]pyrimidin-8-one Method 27  92

6-[[2-fluoro-3- (trifluoromethyl)phenyl]methyl]-1-(hydroxymethyl)-2,3-dihydro-1H- cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one Method 27  93

2-ethyl-7-[[2-fluoro-3- (trifluoromethyl)phenyl]methyl]-N-methyl-5-oxo-thiazolo[3,2- a]pyrimidine-3-carboxamide Method 21  94

2-[7-[[2-fluoro-3- (trifluoromethyl)phenyl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidin-3-yl]cyclopropanecarbonitrile Ex. 207  95

6-[[5-cyclopropyl-3- (trifluoromethyl)pyrazol-1-yl]methyl]-1-(hydroxymethyl)-2,3-dihydro-1H- cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one Method 27  96

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N,2-dimethyl-5-oxo- thiazolo[3,2-a]pyrimidine-3-carboxamide Ex. 28  97

7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-N,2-dimethyl-5-oxo- thiazolo[3,2-a]pyrimidine-3-carboxamide Ex. 28  98

2-[7-[[5-chloro-3- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidin-3-yl]-N-methyl-acetamide Method2  99

2-[7-[[3-chloro-5- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidin-3-yl]-N-methyl-acetamide Method2 100

7-[[2-fluoro-3- (trifluoromethyl)phenyl]methyl]-3-(2-hydroxycyclopropyl)-2-methyl- thiazolo[3,2-a]pyrimidin-5-one Method 20101

2-[7-[2-fluoro-3- (trifluoromethyl)phenoxy]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3- yl]cyclopropanecarbonitrile Ex. 12 102

7-[[5-chloro-3-(trifluoromethyl)pyrazol- 1-yl]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl- thiazolo[3,2-a]pyrimidin-5-oneMethod 15 103

7-[[3-chloro-5-(trifluoromethyl)pyrazol- 1-yl]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl- thiazolo[3,2-a]pyrimidin-5-oneMethod 15 104

2-[7-[[5-chloro-3- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidin-3- yl]cyclopropanecarbonitrileMethod 15 106

7-[[2-fluoro-3- (trifluoromethyl)phenyl]methyl]-N-isopropyl-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidine-3-carboxamide Method21 107

2-fluoro-3-[2-methyl-3-(2- methylcyclopropyl)-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl]oxy-benzonitrile Ex. 12 108

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(1-hydroxy-1-methyl- ethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one Method 18 109

7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(1-hydroxy-1-methyl- ethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one Method 18 110

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(1-hydroxyethyl)-2- methyl-thiazolo[3,2-a]pyrimidin-5-oneMethod 18 111

7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(1-hydroxyethyl)-2- methyl-thiazolo[3,2-a]pyrimidin-5-oneMethod 18 112

7-[[2-fluoro-3- (trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-N-sec-butyl-thiazolo[3,2- a]pyrimidine-3-carboxamide Method21 113

3-[[3-(azetidin-1-yl)-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl]methyl]- 2-fluoro-benzonitrile Method 6114

7-[[5-chloro-3-(trifluoromethyl)pyrazol- 1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carbonitrile Method 17 115

7-[[3-chloro-5-(trifluoromethyl)pyrazol- 1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carbonitrile Method 17 116

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-cyclopropyl-2-methyl- thiazolo[3,2-a]pyrimidin-5-oneMethod 15 117

7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-cyclopropyl-2-methyl- thiazolo[3,2-a]pyrimidin-5-oneMethod 15 118

7-[[5-chloro-3-(trifluoromethyl)pyrazol- 1-yl]methyl]-2-methyl-3-(2-methylcyclopropyl)thiazolo[3,2- a]pyrimidin-5-one Method 15 119

3-acetyl-7-[[5-chloro-3- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5- one Method 18 120

3-acetyl-7-[[3-chloro-5- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5- one Method 18 121

2-chloro-7-[[2-fluoro-3- (trifluoromethyl)phenyl]methyl]-3-(2-methylcyclopropyl)thiazolo[3,2- a]pyrimidin-5-one Method 33 122

7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-pyrimidin-5- yl-thiazolo[3,2-a]pyrimidin-5-oneMethod 15 123

7-[[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidine-3-carboxamide Ex. 28124

7-[[(5-chloro-2-pyridyl)-methyl- amino]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Ex. 28 125

2-[7-[[5-chloro-3- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidin-3- yl]cyclopropanecarbonitrile(cis enantiomer 1) Method 15 126

2-[7-[[5-chloro-3- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidin-3- yl]cyclopropanecarbonitrile(cis enantiomer 2) Method 15 127

7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-2-methoxy-5-oxo- thiazolo[3,2-a]pyrimidine-3-carboxamide Ex. 91 128

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-2-methoxy-5-oxo- thiazolo[3,2-a]pyrimidine-3-carboxamide Ex. 91 129

7-[[5-cyclopropyl-3- (trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-2-methoxy-5-oxo-thiazolo[3,2- a]pyrimidine-3-carboxamide Ex. 91130

7-[[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-2-methoxy-5-oxo-thiazolo[3,2- a]pyrimidine-3-carboxamide Ex. 91131

2-[7-[[2-fluoro-3- (trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin- 3-yl]cyclopropanecarbonitrileMethod 20 132

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-(1H-pyrazol- 5-yl)thiazolo[3,2-a]pyrimidin-5-oneMethod 15 133

7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-(1H-pyrazol- 5-yl)thiazolo[3,2-a]pyrimidin-5-oneMethod 15 134

7-[[5-chloro-3-(trifluoromethyl)pyrazol- 1-yl]methyl]-2-methyl-3-(3-pyridyl)thiazolo[3,2-a]pyrimidin-5-one Method 15 135

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-isopropenyl-2-methyl- thiazolo[3,2-a]pyrimidin-5-oneMethod 15 136

7-[[5-chloro-3-(trifluoromethyl)pyrazol- 1-yl]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl- thiazolo[3,2-a]pyrimidin-5-one(trans enantiomer 1) Method 15 137

7-[[5-chloro-3-(trifluoromethyl)pyrazol- 1-yl]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl- thiazolo[3,2-a]pyrimidin-5-one(trans enantiomer 2) Method 15 138

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(5-fluoro-3-pyridyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one Method 15 139

7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(5-fluoro-3-pyridyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one Method 15 140

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-propanoyl- thiazolo[3,2-a]pyrimidin-5-one Method18 141

7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-propanoyl- thiazolo[3,2-a]pyrimidin-5-one Method18 142

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-thiazol-2-yl- thiazolo[3,2-a]pyrimidin-5-oneMethod 15 143

N-ethyl-7-[[(5-fluoro-2-pyridyl)- methyl-amino]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Ex. 28 144

2-[7-[[5-chloro-3- (trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidin-3-yl]cyclopropanecarbonitrile Ex. 207 145

2-[7-[[3-chloro-5- (trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidin-3-yl]cyclopropanecarbonitrile Ex. 207 146

2-fluoro-3-[[5-oxo-2-(trifluoromethyl)- 3-[2-(trifluoromethyl)cyclopropyl]thiazolo[3,2-a]pyrimidin-7-yl]methyl]benzonitrile Ex. 207 147

N-ethyl-7-[[ethyl-(5-fluoro-2- pyridyl)amino]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Ex. 28 148

N-ethyl-7-[[ethyl(2- pyridyl)amino]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Ex. 28 149

3-(5-chloro-3-pyridyl)-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5- one Method 15 150

3-(5-chloro-3-pyridyl)-7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5- one Method 15 151

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-thiazol-4-yl- thiazolo[3,2-a]pyrimidin-5-oneMethod 15 152

7-[[(5-chloro-2-pyridyl)-ethyl- amino]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Ex. 28 154

7-[[5-chloro-3-(trifluoromethyl)pyrazol- 1-yl]methyl]-2-methyl-3-[2-methylcyclopropyl]thiazolo[3,2- a]pyrimidin-5-one (trans enantiomer 1)Method 15 155

7-[[5-chloro-3-(trifluoromethyl)pyrazol- 1-yl]methyl]-2-methyl-3-[2-methylcyclopropyl]thiazolo[3,2- a]pyrimidin-5-one (trans enantiomer 2)Method 15 156

2-ethoxy-N-ethyl-7-[[2-fluoro-3- (trifluoromethyl)phenyl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Ex. 91 157

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(2-fluoro-3-pyridyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one Method 15 158

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-oxazol-2-yl- thiazolo[3,2-a]pyrimidin-5-oneMethod 15 159

7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-oxazol-2-yl- thiazolo[3,2-a]pyrimidin-5-oneMethod 15 160

7-[[5-chloro-3-(trifluoromethyl)pyrazol- 1-yl]methyl]-2-methyl-3-(trifluoromethyl)thiazolo[3,2- a]pyrimidin-5-one Method 15 161

7-[[3-chloro-5-(trifluoromethyl)pyrazol- 1-yl]methyl]-2-methyl-3-(trifluoromethyl)thiazolo[3,2- a]pyrimidin-5-one Method 15 162

2-[7-[[2-fluoro-3- (trifluoromethyl)phenyl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidin-3-yl]cyclopropanecarbonitrile Ex. 207 163

7-[[(5-chloro-2-pyridyl)-methyl- amino]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl- thiazolo[3,2-a]pyrimidin-5-oneMethod 14 164

7-[(3,5-dichloropyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidine-3-carboxamide Ex. 28 165

N-ethyl-7-[[2-fluoro-3- (trifluoromethyl)phenyl]methyl]-5-oxo-2-(2,2,2-trifluoroethoxy)thiazolo[3,2- a]pyrimidine-3-carboxamide Ex. 91166

3-acetyl-7-[[5-chloro-3- (trifluoromethyl)pyrazol-1-yl]methyl]-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidin-5-one Ex. 207 167

3-acetyl-7-[[3-chloro-5- (trifluoromethyl)pyrazol-1-yl]methyl]-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidin-5-one Ex. 207 168

3-[(4-chloropyrazol-1-yl)methyl]-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1- yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one Method 10 169

7-[[5-chloro-3-(trifluoromethyl)pyrazol- 1-yl]methyl]-3-isopropenyl-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidin-5-one Ex. 207 170

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(1H-imidazol-2-yl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one Ex. 258 171

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-pyrimidin-5-yl-2- (trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one Ex. 207 172

7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-pyrimidin-5-yl-2- (trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one Ex. 207 173

7-[[3-chloro-5-(trifluoromethyl)pyrazol- 1-yl]methyl]-3-(3-pyridyl)-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidin-5-one Ex. 207 174

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-5-oxo-2-(2,2,2- trifluoroethoxy)thiazolo[3,2-a]pyrimidine-3-carboxamide Ex. 91 175

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-ethoxy-N-ethyl-5-oxo- thiazolo[3,2-a]pyrimidine-3-carboxamide Ex. 91 176

7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-ethoxy-N-ethyl-5-oxo- thiazolo[3,2-a]pyrimidine-3-carboxamide Ex. 91 177

7-[[5-chloro-3-(trifluoromethyl)pyrazol- 1-yl]methyl]-2-methyl-3-(2-methylpropanoyl)thiazolo[3,2- a]pyrimidin-5-one Method 18 178

7-[[3-chloro-5-(trifluoromethyl)pyrazol- 1-yl]methyl]-2-methyl-3-(2-methylpropanoyl)thiazolo[3,2- a]pyrimidin-5-one Method 18 179

7-[[2-fluoro-3- (trifluoromethyl)phenyl]methyl]-2-methyl-N-[(1R)-1-methylpropyl]-5- oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide Method 21 180

7-[[2-fluoro-3- (trifluoromethyl)phenyl]methyl]-2-methyl-N-[(1S)-1-methylpropyl]-5-oxo- thiazolo[3,2-a]pyrimidine-3-carboxamide Method 21 191

7-[[(4-chloro-2-pyridyl)-ethyl- amino]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Ex. 28 182

7-[[(5-fluoro-2-pyridyl)-methyl- amino]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl- thiazolo[3,2-a]pyrimidin-5-oneMethod 15 183

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(methoxymethyl)-2- methyl-thiazolo[3,2-a]pyrimidin-5-oneMethod 10 184

7-[[5-chloro-3-(trifluoromethyl)pyrazol- 1-yl]methyl]-3-cyclopropyl-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidin-5-one Ex. 91 185

7-[[5-chloro-3-(trifluoromethyl)pyrazol- 1-yl]methyl]-2-methyl-3-(methylsulfonylmethyl)thiazolo[3,2- a]pyrimidin-5-one Method 10 186

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-(pyrazol-1- ylmethyl)thiazolo[3,2-a]pyrimidin-5-one Method 10 187

2-[7-[[2-chloro-5- (trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin- 3-yl]cyclopropanecarbonitrileMethod 20 188

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-cyclobutyl-2-methyl- thiazolo[3,2-a]pyrimidin-5-one Ex.28 189

7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-cyclobutyl-2-methyl- thiazolo[3,2-a]pyrimidin-5-one Ex.28 190

2-[7-[[(5-chloro-2-pyridyl)-methyl- amino]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3- yl]cyclopropanecarbonitrile Method 14 191

7-[[ethyl-(5-fluoro-2- pyridyl)amino]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl- thiazolo[3,2-a]pyrimidin-5-oneMethod 14 192

3-chloro-7-[[5-chloro-3- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5- one Method 15 193

3-chloro-7-[[3-chloro-5- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5- one Method 15 194

2-[7-[(4,5-difluoro-2-methoxy- phenyl)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3- yl]cyclopropanecarbonitrile Method 23 195

2-[7-[[ethyl-(5-fluoro-2- pyridyl)amino]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3- yl]cyclopropanecarbonitrile Method 14 196

7-[[(5-chloro-2-pyridyl)-ethyl- amino]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl- thiazolo[3,2-a]pyrimidin-5-oneMethod 14 197

5-[7-[[5-chloro-3- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidin-3-yl]pyridine-3-carbonitrileMethod 15 198

7-[[5-chloro-3-(trifluoromethyl)pyrazol- 1-yl]methyl]-2-methyl-3-(2,2,2-trifluoroacetyl)thiazolo[3,2- a]pyrimidin-5-one Method 10 199

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(2-methylcyclopropyl)- 2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one Ex. 207 200

7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(2-methylcyclopropyl)- 2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one Method 15 201

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-pyrimidin-5- yl-thiazolo[3,2-a]pyrimidin-5-oneMethod 15 202

7-[[5-chloro-3-(trifluoromethyl)pyrazol- 1-yl]methyl]-2-ethyl-3-(3-pyridyl)thiazolo[3,2-a]pyrimidin-5-one Method 23 203

7-[[5-chloro-3-(trifluoromethyl)pyrazol- 1-yl]methyl]-2-methyl-3-(2,2,2-trifluoro-1-hydroxy-ethyl)thiazolo[3,2- a]pyrimidin-5-one Method 14 204

7-[[(5-bromo-2-pyridyl)-ethyl- amino]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide Method 14 205

N-ethyl-7-[[ethyl-(5-fluoro-2- pyridyl)amino]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidine-3-carboxamide Method 15 209

2-[7-[[5-methoxy-3- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidin-3- yl]cyclopropanecarbonitrileMethod 15 210

2-[7-[[3-methoxy-5- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidin-3- yl]cyclopropanecarbonitrileMethod 15 211

3-acetyl-7-[[5-chloro-3- (trifluoromethyl)pyrazol-1-yl]methyl]-2-ethyl-thiazolo[3,2-a]pyrimidin-5-one Method 18 212

3-acetyl-7-[[3-chloro-5- (trifluoromethyl)pyrazol-1-yl]methyl]-2-ethyl-thiazolo[3,2-a]pyrimidin-5-one Method 18 213

2-[7-[[5-chloro-3- (trifluoromethyl)pyrazol-1-yl]methyl]-2-ethyl-5-oxo-thiazolo[3,2-a]pyrimidin- 3-yl]cyclopropanecarbonitrileMethod 15 214

2-[7-[[3-chloro-5- (trifluoromethyl)pyrazol-1-yl]methyl]-2-ethyl-5-oxo-thiazolo[3,2-a]pyrimidin- 3-yl]cyclopropanecarbonitrileMethod 15 215

3-bromo-7-[[5-chloro-3- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5- one Method 15 216

3-bromo-7-[[3-chloro-5- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5- one Method 15 217

3-chloro-7-[[5-chloro-3- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methoxy-thiazolo[3,2-a]pyrimidin-5- one Ex. 244 218

3-chloro-7-[[3-chloro-5- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methoxy-thiazolo[3,2-a]pyrimidin-5- one Ex. 244 219

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-methylsulfanyl-2- (trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one Ex. 206 221

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(cyclopropylmethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one Method 15 223

7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(2-hydroxy-1-methyl- ethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one Ex. 222 224

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(cyclopropanecarbonyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5- one Method 10 225

3-bromo-7-[[5-chloro-3- (trifluoromethyl)pyrazol-1-yl]methyl]thiazolo[3,2-a]pyrimidin-5- one Method 15 226

3-bromo-7-[[3-chloro-5- (trifluoromethyl)pyrazol-1-yl]methyl]thiazolo[3,2-a]pyrimidin-5- one Method 15 227

7-[(3-amino-5-chloro-pyrazol-1- yl)methyl]-3-bromo-2-methyl-thiazolo[3,2-a]pyrimidin-5-one Method 15 228

7-[(5-amino-3-chloro-pyrazol-1- yl)methyl]-3-bromo-2-methyl-thiazolo[3,2-a]pyrimidin-5-one Method 15 229

2-[7-[[5-chloro-3- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidin-3-yl]acetonitrile Method 10 230

N-ethyl-7-[[(5-fluoro-2-pyridyl)- methyl-amino]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidine-3-carboxamide Ex. 28 231

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(3,3-difluoroazetidin-1-yl)-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidin-5-one Ex. 206 233

7-[[5-chloro-3-(trifluoromethyl)pyrazol- 1-yl]methyl]-2-methoxy-3-(3-pyridyl)thiazolo[3,2-a]pyrimidin-5-one Ex. 244 234

2-[7-[[5-bromo-3- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidin-3- yl]cyclopropanecarbonitrileMethod 15 235

3-chloro-7-[[5-chloro-3- (trifluoromethyl)pyrazol-1-yl]methyl]thiazolo[3,2-a]pyrimidin-5- one Method 15 236

3-chloro-7-[[3-chloro-5- (trifluoromethyl)pyrazol-1-yl]methyl]thiazolo[3,2-a]pyrimidin-5- one Method 15 237

2-acetyl-7-[[5-chloro-3- (trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-5-oxo-thiazolo[3,2- a]pyrimidine-3-carboxamide Ex. 258 238

2-acetyl-7-[[3-chloro-5- (trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-5-oxo-thiazolo[3,2- a]pyrimidine-3-carboxamide Ex. 258 239

7-[[5-chloro-3-(trifluoromethyl)pyrazol- 1-yl]methyl]-3-(trifluoromethyl)thiazolo[3,2- a]pyrimidin-5-one Method 15 241

2-[7-[[5-chloro-3- (trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidin-3- yl]cyclopropanecarbonitrile Method 15242

3-acetyl-7-[[5-chloro-3- (trifluoromethyl)pyrazol-1-yl]methyl]thiazolo[3,2-a]pyrimidin-5- one Method 18 243

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(2,2,2-trifluoroethoxy)- 2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one Ex. 206 245

3-acetyl-7-[[3-chloro-5- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methoxy-thiazolo[3,2-a]pyrimidin-5- one Ex. 244 246

3-bromo-7-[(5-chloro-3-nitro-pyrazol-1-yl)methyl]-2-methyl-thiazolo[3,2- a]pyrimidin-5-one Method 15 247

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(1H-pyrazol-5-yl)-2- (trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one Ex. 207 248

7-[[5-chloro-3-(trifluoromethyl)pyrazol- 1-yl]methyl]-3-thiazol-4-yl-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidin-5-one Ex. 207 249

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(5-fluoro-3-pyridyl)-2- (trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one Ex. 207    251A

2-[7-[[5-chloro-3- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidin-3-yl]propanenitrile Ex. 222 252

2-[7-[[3-chloro-5- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidin-3-yl]propanenitrile Ex. 222 253

2-fluoro-3-[[3-[2-methylcyclopropyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-7-yl]methyl]benzonitrile Ex. 207 254

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(3-fluoroazetidin-1-yl)- 2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one Ex. 206 255

3-(5-chloro-3-pyridyl)-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]- 2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one Ex. 207 256

7-[(3,5-dichloropyrazol-1-yl)methyl]-N- ethyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidine-3-carboxamide Ex. 28 257

3-[[3-acetyl-5-oxo-2- (trifluoromethyl)thiazolo[3,2-a]pyrimidin-7-yl]methyl]-2-fluoro- benzonitrile Ex. 207 259

7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-(difluoromethyl)-N-ethyl-5-oxo-thiazolo[3,2-a]pyrimidine- 3-carboxamide Ex. 258 260

(Z)-3-[7-[(N-ethyl-4-fluoro- anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]prop-2- enenitrile Method 5 261

(E)-3-[7-[(N-ethyl-4-fluoro- anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]prop-2- enamide Method 5 262

(E)-3-[7-[[5-chloro-3- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidin-3-yl]prop-2-enenitrile Method 5263

(Z)-3-[7-[[5-chloro-3- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidin-3-yl]prop-2-enenitrile Method 5264

(E)-3-[7-[[5-chloro-3- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidin-3-yl]prop-2-enamide Method 5265

N-ethyl-7-[[5-isobutyl-3- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidine-3-carboxamide Ex. 28 268

2-[2-chloro-7-[[3-chloro-5- (trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidin-3- yl]cyclopropanecarbonitrile Ex. 267269

7-[[5-chloro-3-(trifluoromethyl)pyrazol- 1-yl]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2- (trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one (trans enantiomer 1) Ex. 207 270

7-[[5-chloro-3-(trifluoromethyl)pyrazol- 1-yl]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2- (trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one (trans enantiomer 2) Ex. 207 271

2-[7-[(4-chloro-1-methyl-pyrazol-3- yl)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3- yl]cyclopropanecarbonitrile Method 20 272

2-[2-methyl-5-oxo-7-[[3- (trifluoromethyl)pyrazol-1-yl]methyl]thiazolo[3,2-a]pyrimidin-3- yl]cyclopropanecarbonitrile (cisenantiomer 1) Method 15 273

2-[2-methyl-5-oxo-7-[[3- (trifluoromethyl)pyrazol-1-yl]methyl]thiazolo[3,2-a]pyrimidin-3- yl]cyclopropanecarbonitrile (cisenantiomer 2) Method 15 274

2-[7-[[5-bromo-3- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidin-3- yl]cyclopropanecarbonitrile(cis enantiomer 1) Method 15 275

2-[7-[[5-bromo-3- (trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidin-3- yl]cyclopropanecarbonitrile(cis enantiomer 2) Method 15 276

2-[7-[[5-chloro-3- (trifluoromethyl)pyrazol-1-yl]methyl]-6-fluoro-5-oxo-2- (trifluoromethyl)thiazolo[3,2- a]pyrimidin-3-yl]cyclopropanecarbonitrile (cis enantiomer 1) Ex. 207 277

2-[7-[[5-chloro-3- (trifluoromethyl)pyrazol-1-yl]methyl]-6-fluoro-5-oxo-2- (trifluoromethyl)thiazolo[3,2- a]pyrimidin-3-yl]cyclopropanecarbonitrile (cis enantiomer 2) Ex. 207 278

2-[2-methyl-7-[[1-methyl-4- (trifluoromethyl)imidazol-2-yl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidin-3- yl]cyclopropanecarbonitrile Ex. 24 279

(E)-3-[7-[(N-ethyl-4-fluoro- anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]prop-2- enenitrile Method 5

The following compounds were prepared using methods analogous to thosedescribed herein. Satisfactory analytical data was obtained for eachcompound.

Ex. Structure Name 280

7-[(4-fluorophenoxy)methyl]-3-[[2-hydroxyethyl(methyl)amino]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 281

7-[(4-fluorophenoxy)methyl]-3-[(2-hydroxyethylamino)methyl]-2-methyl-thiazolo[3,2- a]pyrimidin-5-one 282

2-[7-[(4-fluorophenoxy)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N,N-dimethyl- acetamide 283

7-[(2-cyano-4,5-difluoro-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide 284

7-[(2-cyclopropyl-4,5-difluoro-phenyl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide 285

3-[2-(azetidin-1-yl)-2-oxo-ethyl]-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl- thiazolo[3,2-alpyrimidin-5-one286

7-[(4-fluorophenoxy)methyl]-2-methyl-3-(4H-1,2,4-triazol-3-ylmethyl)thiazolo[3,2-a]pyrimidin-5-one 287

2-[7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N- methyl-propanamide 288

3-[7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N- methyl-propanamide 289

7-[[5-chloro-2-(trifluoromethyl)phenyl]methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide 290

7-[(5-ethyl-1,3-benzoxazol-6-yl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide 291

7-[(3-chloropyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 292

7-[(5-chloropyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 293

2-[7-[(3-cyano-2-fluoro-phenyl)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl- acetamide 294

N-ethyl-7-[[2-fluoro-3-(1- hydroxypropyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 295

7-[(4,5-difluoro-2-oxazol-2-yl-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide 296

2-fluoro-3-[(2-methyl-5-oxo-3-propanoyl-thiazolo[3,2-a]pyrimidin-7-yl)methyl]benzonitrile 297

7-[[4,5-difluoro-2-(trifluoromethyl)phenyl]methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide 298

N,2-dimethyl-5-oxo-7-[3-(trifluoromethyl)phenoxy]thiazolo[3,2-a]pyrimidine- 3-carboxamide 299

7-[[2-chloro-5-(trifluoromethyl)phenyl]methyl]-N-ethyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidine-3-carboxamide300

7-[[2-chloro-5-(trifluoromethyl)phenyl]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide 301

7-[[2-chloro-5-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-N-(2,2,2-trifluoroethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide 302

N-ethyl-2-methyl-5-oxo-7-[3-(trifluoromethyl)phenoxy]thiazolo[3,2-a]pyrimidine- 3-carboxamide 303

3-[(2-chloro-3-cyclopropyl-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl)methyl]-2-fluoro-benzonitrile 304

7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-3-(pyrazol-1-ylmethyl)thiazolo[3,2- a]pyrimidin-5-one 305

N,2-dimethyl-7-[[3-methyl-4-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 306

N,2-dimethyl-7-[[5-methyl-4-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 307

2-fluoro-3-[(8-oxo-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-6- yl)methyl]benzonitrile 308

7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-3-[hydroxy(thiazol-2-yl)methyl]-2-methyl- thiazolo[3,2-a]pyrimidin-5-one309

2-fluoro-3-[(3-methyl-8-oxo-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-6- yl)methyl]benzonitrile 310

2-[7-[(4-fluorophenoxy)methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]-N- methyl-acetamide 311

2-fluoro-3-[(8-oxo-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-6- yl)oxy]benzonitrile 312

2-fluoro-3-[[1-(hydroxymethyl)-8-oxo-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-6- yl]methyl]benzonitrile 313

7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-N-(2-hydroxy-1-methyl-ethyl)-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 314

3-[[3-(2,3-dimethylcyclopropyl)-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl]methyl]-2-fluoro- benzonitrile 315

6-[[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-1-(hydroxymethyl)-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one 316

7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)thiazolo[3,2-a]pyrimidin-5-one 317

N-ethyl-6-fluoro-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3- carboxamide 318

7-[(4-fluorophenoxy)methyl]-5-oxo-N-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide 319

N-cyclopentyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 320

7-[(4,5-dichloropyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide 321

7-[(3,4-dichloropyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide 322

N-ethyl-2-methyl-7-[[methyl(thiazol-2-yl)amino]methyl]-5-oxo-thiazolo[3,2-a]pyrimidine- 3-carboxamide 323

7-[(4-chloropyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 324

N-ethyl-2-methyl-7-[[methyl-(1-methylpyrazol-4-yl)amino]methyl]-5-oxo-thiazolo[3,2-a]pyrimidine- 3-carboxamide 325

7-[(4-fluorophenoxy)methyl]-2-(trifluoromethyl)-3-[2-(trifluoromethyl)cyclopropyl]thiazolo[3,2- a]pyrimidin-5-one 326

7-[[(3-ethoxy-2-pyridyl)-methyl-amino]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide 327

7-[[(3,5-dimethylisoxazol-4-yl)-methyl-amino]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 328

3-cyclopropyl-7-[(4-fluorophenoxy)methyl]-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 329

7-[(4-fluorophenoxy)methyl]-3-pyrimidin-5-yl-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 330

7-[(4-fluorophenoxy)methyl]-3-[2- (hydroxymethyl)cyclopropyl]-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 331

7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-3-(4-methyl-1,2,4-triazol-3-yl)thiazolo[3,2- a]pyrimidin-5-one332

2-fluoro-3-[[5-oxo-2-(trifluoromethyl)-3-[2-(trifluoromethyl)cyclopropyl]thiazolo[3,2-a]pyrimidin-7-yl]methyl]benzonitrile 333

N-ethyl-7-[[ethyl(4-pyridyl)amino]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide 334

N-ethyl-7-[[ethyl(3-pyridyl)amino]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide 335

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(2-methoxy-3-pyridyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 336

2-[7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile 337

7-[[3-chloro-5-(trifluoromethyl)pyrazol-1- yl]methyl]-3-isopropenyl-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 338

3-(5-chloro-3-pyridyl)-7-[[(5-chloro-2-pyridyl)-methyl-amino]methyl]-2-methyl-thiazolo[3,2- a]pyrimidin-5-one 339

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1- yl]methyl]-3-(3-pyridyl)-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 340

7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-5-oxo-2-(2,2,2-trifluoroethoxy)thiazolo[3,2-a]pyrimidine-3- carboxamide 341

7-[[3-chloro-6-(trifluoromethyl)-2-pyridyl]methyl]-2-methyl-3-(2-methylcyclopropyl)thiazolo[3,2- a]pyrimidin-5-one 342

7-[(5-chloro-2-pyridyl)oxymethyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide 343

7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-ethyl-3-(3-pyridyl)thiazolo[3,2- a]pyrimidin-5-one 344

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-pyrrolidin-1-yl-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 345

N-ethyl-7-[[(5-methoxy-2-pyridyl)-methyl-amino]methyl]-2-methyl-5-oxo-thiazolo[3,2- a]pyrimidine-3-carboxamide346

3-(2-chloro-3-pyridyl)-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 347

3-(2-chloro-3-pyridyl)-7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 348

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(3-pyridyl)thiazolo[3,2-a]pyrimidin-5- one 349

7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(3-pyridyl)thiazolo[3,2-a]pyrimidin-5- one 350

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(3-methoxyazetidin-1-yl)-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin 351

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(cyclopropylmethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one 352

5-[7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3- yl]pyridine-3-carbonitrile 353

2-fluoro-3-[[3-[2-methylcyclopropyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-7- yl]methyl]benzonitrile 354

7-[(3,5-diisopropylpyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3- carboxamide 355

2-[7-[(4-chloro-2-methyl-pyrazol-3-yl)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3- yl]cyclopropanecarbonitrile 356

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(2-methylazetidin-1-yl)-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one 357

2-[7-[(3,5-dichloropyrazol-1-yl)methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3- yl]cyclopropanecarbonitrile(cis enantiomer 1) 358

2-[7-[(3,5-dichloropyrazol-1-yl)methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3- yl]cyclopropanecarbonitrile(cis enantiomer 2) 359

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-[2-(2-hydroxyethyl)cyclopropyl]-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one (trans enantiomer 1) 360

7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-[2-(2-hydroxyethyl)cyclopropyl]-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one (trans enantiomer 2) 361

3-chloro-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-(trifluoromethyl)thiazolo[3,2- a]pyrimidin-5-one 362

5-chloro-1-[[3-[2-methylcyclopropyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-7-yl]methyl]pyrazole-3-carbonitrile (cis enantiomer 1) 363

5-chloro-1-[[3-[2-methylcyclopropyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-7-yl]methyl]pyrazole-3-carbonitrile (cis enantiomer 2) 364

5-chloro-2-[[3-[2-methylcyclopropyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-7-yl]methyl]pyrazole-3-carbonitrile 365

7-[[5-ethoxy-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide 366

N-ethyl-7-[[5-isobutyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide 367

2-[2-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]cyclopropyl]acetonitrile (trans enantiomer 1) 368

2-[2-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]cyclopropyl]acetonitrile (trans enantiomer 2)

It is understood that the person skilled in the art will be able toprepare the compounds of the present invention using methods known inthe art along with the general method of synthesis described herein.

Assay 1: Cell-Based Assay

HEK cells stably transfected with tetracycline inducible hNR1 and hNR2Awere seeded into clear bottom 384 well poly-D-lysine coated plates(2.5×10⁴ cells per well) in Minimum Essential Media (MEM; without L-)including 7.5 μg mL⁻¹ doxycycline and 500 μM (+)-ketamine. The cellswere incubated at 37° C. in 5% CO₂ for 24 h. For measurement of changesin cytosolic calcium, the seeding media was removed and the cellsincubated at 37° C. for 60 min with 1× Becton Dickinson Calcium AssayKit reagent in Hanks Balanced Salt Solution (HBSS; w/o magnesium,including 1.8 mM calcium, 0.65 mg ml⁻¹ probenecid and 10 μM(+)-ketamine, pH 7.15) then allowed to equilibrate to rt for 30 min.Concentration-effect curves to Positive Allosteric Modulators (PAMs)were constructed by adding different concentrations (with 30 μM glycineand 300 nM L-glutamate (EC₃₀)) to different wells in HBSS. Compoundswere added after a 10 second baseline read and maximum level of relativefluorescence units (RFU) was measured over a 5 min period. Responseswere scaled relative to 100 μM L-glutamate maximal response (100%) and 0μM L-glutamate (0%). EC₅₀ values are provided for compounds reachingmaximal response plateaus, and the max % (EC₅₀ (- -)) only if no plateauwas reached.

A four-parameter Hill equation was fitted to individualconcentration-effect curves:

$Y = {S_{0} + \frac{S_{\inf} - S_{0}}{1 + \left( \frac{10^{\log\;{AC}\; 50}}{10^{c}} \right)^{n}}}$in which Y, S₀, S_(inf), AC₅₀, n and c were effect, lower-asymptote,upper-asymptote, mid-point location, slope parameter, and concentrationrespectively.

Data for compounds tested in this assay are shown below in Table 2.

TABLE 2 No. EC₅₀ (uM) Max % 1.1 9.6   63% 1.2 —   92% 1.3 —   45% 1.411.2 59.5% 1.5 23 51.4% 1.6 31.6   64% 1.7 27 44.8% 1.8 26.3 47.4% 1.9 —99.5% 1.10 —   44% 1.11 —   73% 1.12 — 45.5% 1.13 — 41.6% 1.14 — 42.7%1.15 — 55.1% 1.16 — 56.5% 1.17 4 68.6% 2.1 5.2 51.3% 2.2 — 96.5% 2.312.6 49.8% 2.4 3.0 44.6% 2.5 32.9  115% 2.6 19.6 59.9% 2.7 26 61.3% 2.8—  137% 2.9 — 56.4% 2.10 —  119% 2.11 — 87.4% 3.1 41 56.2% 3.2 10.142.7% 3.3 — 61.8% 3.4 — 44.6% 3.5 — 65.6% 3.6 —   68% 4.1 5.1  141% 4.21.3  137% 4.3 20.5 71.6% 4.4 2.5  138% 4.5 5.7 42.2% 4.6 7.7  128% 4.75.8  134% 4.8 4.4 99.3% 4.9 4.4  123% 4.10 4.3  108% 4.11 4.8 40.8% 4.1230.6  127% 4.13 31.1 72.8% 4.14 7.8   93% 4.15 13.9   50% 4.16 — 46.2%4.17 — 40.3% 4.18 5.0  102% 4.19 9.0 46.9% 4.20 2.4 93.9% 4.21 16.3 47.4 4.22 —  84.2 4.23 26.5 62.9% 4.24 2.1   80% 4.25 2.8  109% 4.26 — 98.8 4.27 —  103% 4.28 3.4   89% 4.29 17.5  134% 4.30 15.5 75.4% 4.31 —43.3% 4.32 — 50.2% 4.33 13.8  121% 4.34 — 49.2% 5.1 0.560 145.1  5.2 5.7 148% 5.3 2.2  177% 5.4 0.956  172% 5.5 2.4  168% 5.6 0.766  164% 5.70.867  160% 5.8 0.669  156% 5.9 1.3  143% 5.10 18  133% 5.11 2.9  118%5.12 —  106% 5.13 — 87.9% 5.14 7.5  111% 5.15 7  144% 5.16 2.5  157%5.17 0.108  176% 5.18 0.091  164% 5.19 1.7  141% 5.20 0.815  157% 5.210.584  141% 5.22 1.6  142% 5.23 2.6  135% 5.24 0.731  142% 5.25 0.7141   5.26 0.563  149% 5.27 1.1  139% 5.28 .0952  176% 5.29 0.445  147%5.30 4.3  132% 5.31 2.7  132% 5.32 4.3  123% 5.33 4.2 120   5.34 2.8 118% 5.35 2.7  136% 5.36 — 61.3% 5.37 0.515  152% 5.38 1.1  147% 5.390.952  167% 5.40 1.9  149% 5.41 2  125% 5.42 0.0329  162% 5.43 0.821 145% 5.44 1.1  158% 5.45 0.214  139% 5.46 3.8  155% 5.47 0.976  151%5.48 6.2  136% 5.49 12.9  127% 5.50 — 96.8% 5.51 40.7 80.3% 5.52 1.6  58% 5.53 1.3  153% 5.54 51.5  129% 5.55 4.7  111% 5.56 —  110% 5.576.4  120% 5.58 5.1  120% 6.1 10  123% 6.2 5  121% 6.3 10.1 91.9% 7.10.853  184% 7.2 0.612  134% 7.3 0.376  156% 7.4 5.7  166% 7.5 2.1  162%7.6 3.7  151% 7.7 21  148% 7.8 2.5  126% 7.9 1.3  121% 8.1 5.2  146% 8.27.2  122% 8.3 1.3  150% 8.4 0.569  164% 8.5 16.9  114% 8.6 — 60.5% 8.7 —81.4% 8.8 8.7  108% 8.9 11.1  124% 8.10 12.5  127% 8.11 2.7  154% 8.120.385  161% 8.13 2.2  162% 8.14 1.1  154% 8.15 2.3  138% 8.16 13  137%9.1 — 48.1% 9.2 2.9  117% 9.3 7.0  108% 9.4 9.2  114% 10.1 4.4  130%10.2 5.3  110% 10.3 0.535  177% 10.4 0.593  186% 10.5 0.495  158% 10.60.548  176% 10.7 23.4  127% 10.8 — 63.5% 10.9 — 72.1% 10.10 18.8  132%10.11 1.2  167% 10.12 2.1  149% 10.13 0.345  165% 10.14 1.5  172% 10.151.3  156% 10.16 2.7  147% 10.17 1.2  174% 10.18 16.9 88.2% 10.19 0.837 165% 10.20 2.2  178% 10.21 —  117% 10.22 7.5  156% 10.23 22.9  169%10.24 8.9  160% 10.25 0.345  165% 11.1 2  159% 11.2 —  107% 11.3 3.2 132% 11.4 —  103% 11.5 4.6  167% 11.6 5.0  133% 12.1 0.723  166% 12.20.27  192% 12.3 1.6  183% 12.4 0.591  176% 12.5 0.974  153% 13.1 0.434 161% 13.2 0.913  130% 13.3 0.783  137% 13.4 0.777  185% 13.5 1  152%13.6 1.4  125% 13.7 0.547  137% 13.8 — 61.2% 13.9 5.0  166% 14.1 2.6 163% 14.2 0.122  205% 15.1 2.2  144% 15.2 1  167% 15.3 0.489  144% 15.40.782  137% 15.5 1.7  131% 15.6 9.2  138% 15.7 0.826  158% 15.8 30.8 122% 15.9 18.6  117% 15.10 3.1  133% 15.11 0.151  159% 15.12 2.5  143%15.13 — 67.6% 15.14 3.1  159% 15.15 — 61.9% 15.16 17.7  115% 15.17 3.4 137% 15.18 10.5  143% 15.19 0.512  126% 15.20 0.314  153% 15.21 1.6 161% 15.22 0.704  149% 15.23 1.9  143% 15.24 1.4  138% 15.25 16.5  137%15.26 3.8  123% 15.27 12.3  137% 15.28 — 80.8% 15.29 7  135% 15.30 22 116% 15.31 — 57.8% 15.32 — 94.8% 15.33 18.8 51.8% 15.34 — 48.2% 16.12.3  140% 16.2 11.7  110% 16.3 1.4  160% 16.4 9.2  130% 16.5 10.6  149%16.6 5.5  140% 16.7 36.2 67.5% 17.1 —  107% 17.2 2  119% 17.3 —  104%18.1 — 94.8% 18.2 2.2  144% 18.3 25.4  129% 18.4 —  127% 18.5 — 40.7%19.1 12.2  116% 19.2 — 64.2% 20.1 3.1  137% 20.2 7.4  145% 20.3 1.8 148% 20.4 8.5  147% 20.5 24  124% 20.6 7.2  137% 20.7 10.8  137% 20.819  134% 20.9 13.9  133% 20.10 9.1  127% 20.11 31.2 78.7% 20.12 —   74%20.13 5.8  146% 21.1 — 96.6% 21.2 21.6  133% 21.3 7.6  131% 21.4 7.4 129% 21.5 18.9  124% 21.6 45.3  114% 21.7 —  100% 21.8 — 99.3% 21.9 —90.1% 21.10 — 70.3% 21.11 —   47% 21.12 6.7  112% 21.13 12.3  131% 21.1411  112% 21.15 —  112% 21.16 14.3  107% 21.17 23.7  107% 21.18 — 58.521.19 7.4  145% 21.20 5.2  114% 21.21 33.6  134% 21.22 — 60.1% 21.23 6.5 107% 21.24 34.5  102% 21.25 3.9  105% 21.26 — 76.5% 21.27 16  122%21.28 11.4  126% 21.29 4.7 98.2% 21.30 —  100% 21.31 — 88.8% 21.32 —84.3% 21.33 — 82.5% 21.34 — 79.9% 21.35 — 77.8% 21.36 — 71.8% 21.37 —68.4% 21.38 — 66.5% 21.39 — 62.6% 21.40 — 61.6% 21.41 — 59.7% 21.42 —54.5% 21.43 — 53.5% 21.44 — 51.9% 21.45 — 49.1% 21.46 — 43.2% 21.47 — 103% 21.48 8.2  100% 21.49 — 82.3% 21.50 — 76.1 21.51 — 75.0 21.52 —72.9% 21.53 —   49% 21.54 —   46% 21.55 — 43.8 21.56 —   41% 21.57 —64.1% 21.58 —  46.1 21.59 — 42.5% 21.60 —   78% 21.61 33.1  131% 21.62 —45.6% 21.63 —  124% 21.64 —  120% 21.65 — 96.3% 21.66 — 92.4% 21.67 —  75% 21.68 4.2  111% 22.1 — 96.9% 22.2 — 41.4% 23.1 18.1  124% 23.2 2.6 134% 23.3 14.8  133% 23.4 6.5  124% 24.1 — 78.5% 24.2 —  116% 24.3 —87.7% 24.4 15.3  103% 24.5 — 59.3% 24.6 — 50.5 24.7 — 47.4% 24.8 8.994.8% 24.9 — 48.5% 25.1 18.7 86.2% 25.2 15.2  140% 26.1 — 80.6% 26.2 9  71% 27.1 — 45.6% 27.2 — 83.2% 27.3 — 93.3% 27.4 — 58.4% 27.5 30.453.2% 27.6 — 91.6% 27.7 26.5 68.5% 27.8 30.4 53.2% 27.9 — 47.8% 27.1029.1  131% 27.11 25.3 93.8% 27.12 40.8 41.4% 27.13 — 48.8% 27.14 44.5  93% 27.15 — 65.3%

Additional data for compounds tested in this assay are shown in Table 3.

Ex. EC₅₀ (uM) Max %  1 0.932 84.0  2 33.7 50.6  3 10.9 55.9  4 3.88 47.5 5 15.1 105  6 0.753 66.8  7 9.73 77.9  8 2.55 86.5  9 8.04 86.4  100.471 138  11 1.14 78.9  12 2.05 113  13 0.858 89.9  14 1.56 56.2  159.02 91.5  16 15.5 88.0  17 7.04 176  18 2.25 192  19 5.45 99.5  20 10.2136  21 7.88 112  22 4.13 172  23 3.48 90.0  24 1.33 129  25 0.292 204 26 4.82 130  27 10.6 126  28 0.388 125  29 1.76 165  30 2.57 106  314.17 111  32 5.95 110  33 6.43 75.8  34 24.5 78.4  35 3.99 70.7  36 1.7280.5  37 9.02 69.4  38 0.533 129  39 6.1 101  40 1.32 61.4  41 4.78 101 42 1.57 105  43 0.362 131  44 0.685 114  45 1.25 130  46 7.04 123  475.14 89.3  48 7.66 92.3  49 17.5 85.2  50 6.4 95.2  51 3.16 62.5  528.76 129  53 0.635 162  54 2.2 96.2  55 1.16 136  56 2.27 139  57 0.627174  58 6.53 126  59 8.22 96.7  60 3.22 106  61 8.06 127  62 24.6 108 63 3.71 94.5  64 12.1 114  65 0.551 128  66 1.69 149  67 36.6 119  6830.4 105  69 11.2 114  70 2.92 68.7  71 1.37 61.6  72 62.6 41.0  73 40.153.9  74 0.507 148  75 28.9 71.9  76 0.436 145  77 0.271 129  78 2.96174  79 14.3 56.5  80 12.2 43.1  81 52.0 53.8  82 0.0787 192  83 0.154185  84 11.2 109  85 2.39 128  86 10.5 114  87 42.0 92.4  88 3.7 118  899.04 79.2  90 1.22 45.7  91 1.03 89.4  92 47.1 94.5  93 1.83 120  942.08 125  95 9.2 135  96 1.21 119  97 5.11 154  98 1.57 130  99 3.69 148100 11.6 94.1 101 3.71 107 102 0.0547 129 103 0.251 151 104 0.0341 137105 3.9 96.1 106 3.4 69.7 107 0.994 121 108 0.247 111 109 0.734 121 1101.88 126 111 6.0 143 112 0.825 55.7 113 2.37 69.3 114 1.34 116 115 2.75128 116 0.351 101 117 1.03 107 118 0.169 128 119 0.325 131 120 0.995 151121 17.6 38.0 122 9.14 109 123 2.59 110 124 5.9 108 125 0.0278 154 1260.249 125 127 4.87 155 128 0.682 108 129 0.774 149 130 6.86 102 1310.681 113 132 2.04 119 133 10.1 135 134 0.501 76.6 135 0.397 115 1360.0391 142 137 0.42 129 138 0.775 104 139 6.36 124 140 0.147 129 1410.328 131 142 2.09 126 143 12.0 137 144 0.0411 151 145 0.132 175 1460.156 140 147 1.98 179 148 20.8 159 149 0.729 107 150 17.3 114 151 0.538115 152 2.85 140 153 73.5 100 154 0.504 126 155 0.0616 136 156 1.47 74.2157 13.0 99.8 158 1.42 130 159 7.59 149 160 0.753 133 161 1.49 141 1620.199 130 163 0.359 143 164 0.562 131 165 1.37 46.3 166 2.69 126 1675.26 132 168 34.1 73.3 169 7.46 108 170 0.814 135 171 1.21 67.5 172 27.683.3 173 24.7 78.6 174 1.67 90.5 175 0.864 90.6 176 8.92 131 177 0.123133 178 0.354 163 179 0.698 54.1 180 2.94 59.1 191 7.34 120 182 0.175169 183 5.29 129 184 9.99 118 185 17.8 97.9 186 3.85 94.1 187 11.1 104188 3.14 129 189 7.45 121 190 0.779 136 191 0.172 187 192 0.198 96.3 1930.243 80.9 194 1.28 117 195 0.0742 177 196 0.0642 171 197 0.327 89.8 1980.201 108 199 1.39 119 200 3.13 124 201 1.4 88.4 202 23.9 100 203 5.85135 204 5.12 137 205 1.12 163 206 7.19 121 207 0.0074 150 208 0.37 120209 0.0666 157 210 8.92 161 211 0.31 123 212 5.84 133 213 0.066 152 2140.18 154 215 0.0911 95.6 216 0.0594 64.9 217 4.74 125 218 83.0 112 21910.5 118 220 47.0 95.6 221 3.76 96.5 222 2.92 115 223 10.9 128 224 0.366115 225 8.69 99.6 226 1.42 48.4 227 13.0 59.3 228 32.2 66.5 229 6.46 107230 6.86 130 231 61.3 116 233 6.14 98.6 234 0.0342 163 235 21.2 127 23644.5 103 237 0.889 98.7 238 2.32 123 239 14.2 131 240 37.1 120 241 0.313134 242 11.4 134 243 0.864 122 244 0.392 134 245 0.409 139 246 0.0999148 247 7.7 108 248 1.45 124 249 6.33 99.2 250 13.8 111 251 0.42 133  251A 2.62 106 252 5.76 140 253 9.95 111 254 1.37 104 255 7.86 66.2 2560.611 145 257 20.5 93.5 258 0.227 133 259 0.749 159 260 2.45 138 2611.54 126 262 1.11 112 263 0.501 117 264 5.09 82 265 4.84 101 266 0.0249158 267 0.157 141 268 0.182 166 269 0.0831 144 270 0.518 120 271 3.57136 272 0.252 143 273 2.08 124 274 0.012 275 0.0737 276 0.0364 156 2770.155 140 278 10.6 129 279 1.82 141 280 — 28.3 281 — 30.9 282 — 41.2 283— 56.2 284 — 149 285 — 38.0 286 — 59.0 287 — 123 288 — 121 289 — 129 290— 50.5 291 — 86.6 292 — 46.3 293 — 96.3 294 — 82.8 295 — 49.4 296 — 111297 — 93.1 298 — 82.3 299 — 53.1 300 — 72.1 301 — 35.8 302 — 85.4 303 —116 304 — 34.8 305 — 32.9 306 — 32.2 307 — 41.7 308 — 35.3 309 — 47.5310 — 32.5 311 — 28.9 312 — 67.0 313 — 88.2 314 — 98.4 315 — 54.4 316 —49.0 317 — 51.1 318 — 27.0 319 — 28.2 320 — 26.9 321 — 26.6 322 — 36.1323 — 53.7 324 — 62.2 325 — 30.9 326 — 36.2 327 — 35.5 328 — 39.3 329 —29.3 330 — 38.3 331 — 47.5 332 — 75.4 333 — 42.3 334 — 48.0 335 — 53.8336 — 81.5 337 — 103 338 — 65.5 339 — 71.5 340 — 131 341 — 95.2 342 —66.1 343 — 103 344 — 38.4 345 — 32.3 346 — 51.1 347 — 41.1 348 — 82.1349 — 35.4 350 — 87.9 351 3.76 96.5 352 — 83.7 353 — 34.9 354 — NT 355 —46.9

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand other variations thereof will be apparent to those of ordinary skillin the art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

The invention claimed is:
 1. A method of treating a subject sufferingfrom or diagnosed with depression or anxiety mediated by NR2A activity,comprising administering to the subject in need of such treatment aneffective amount a compound of Formula (II):

wherein R^(a) is C₁₋₆alkyl or C₂₋₆alkenyl, each optionally substitutedwith one or more R^(b) substituents; C₂₋₆alkynyl; halo; —C(O)R^(c);—NR^(d)R^(e); —C(O)NR^(d)R^(e); —C(S)NR^(d)R^(e); —C(═N—OH)—C₁₋₄alkyl;—OC₁₋₄alkyl; —OC₁₋₄haloalkyl; —SC₁₋₄alkyl; SO₂C₁₋₄alkyl; cyano;C₃₋₆cycloalkyl optionally substituted with one or more R^(f)substituents; or a phenyl, monocyclic heteroaryl, or heterocycloalkylring, each ring optionally substituted with one or more R^(g)substituents; wherein each R^(b) substituent is independently selectedfrom the group consisting of —OH, —C₁₋₄alkoxy, —NR^(d)R^(e),—C(O)NR^(d)R^(e), —SC₁₋₄alkyl, —SO₂C₁₋₄alkyl, cyano, halo,C₃₋₆cycloalkyl, and monocyclic heteroaryl; R^(c) is C₁₋₄alkyl,—C₁₋₄haloalkyl, C₃₋₆cycloalkyl, or a monocyclic, carbon-linkedheterocycloalkyl; R^(d) is H or C₁₋₄alkyl; R^(e) is H; C₁₋₄alkyloptionally substituted with —CN, —CF₃, —OH, or a monocyclicheterocycloalkyl; C₃₋₆cycloalkyl; —OH; or —OC₁₋₄alkoxy; or R^(d) andR^(e) taken together with the nitrogen to which they are attached form aheterocycloalkyl, optionally substituted with C₁₋₄alkyl or OH; eachR^(f) substituent is independently selected from the group consistingof: C₁₋₄alkyl optionally substituted with —OH, cyano, or C₁₋₄alkoxy;—OH; halo; C₁₋₄haloalkyl; —CONH₂; and cyano; and each R^(g) substituentis independently selected from the group consisting of C₁₋₄alkyl, CF₃,halo, —NH₂, —OCH₃, cyano, and —OH; R¹ is selected from the groupconsisting of H, C₁₋₆-alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, halo,—OC₁₋₄alkyl, —OC₁₋₄haloalkyl, cyano, and —C(O)C₁₋₄alkyl; or R^(a) and R¹taken together with the carbons to which they are attached form a 5- to7-membered ring, optionally containing an O or NH, and optionallysubstituted with one or more R^(h) substituents; wherein each R^(h)substituent is independently —C(O)NR^(i)R^(j), cyano, or is C₁₋₄alkyloptionally substituted with —OH, OCH₃, cyano, or —C(O)NR^(i)R^(j); ortwo R^(h) groups attached to the same carbon and taken together with thecarbon to which they are attached form a carbonyl or a C₃₋₆cycloalkyl;wherein R^(i) and R^(j) are each independently H or C₁₋₄alkyl; R² is—R^(m), —OR^(m), or —NR^(m)R^(n); wherein R^(m) is phenyl, naphthyl,pyridyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, triazolyl,imidazolyl, furanyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl,isothiazolyl, indolyl, indazolyl, quinolinyl, or isoquinolinyl, eachoptionally substituted with one or more R^(s) substituents; wherein eachR^(s) substituent is independently selected from the group consisting ofC₁₋₄alkyl, C₂₋₄alkenyl (optionally substituted with halo), C₂₋₄alkynyl,C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄alkyl-OH, C₁₋₄haloalkoxy, halo, cyano,C₃₋₆cycloalkyl (optionally substituted with —OH or halo), monocyclicheteroaryl, —NH₂, —NO₂, NHSO₂C₁₋₄alkyl, and —SO₂C₁₋₄alkyl; R^(n) is H,C₁₋₄haloalkyl, or C₁₋₄alkyl optionally substituted with —OH orC₁₋₄alkoxy; or R^(m) and R^(n) taken together with the nitrogen to whichthey are attached form a pyrrolidine or piperidine ring, optionallysubstituted with C₁₋₄alkyl and optionally fused to phenyl, wherein saidphenyl is optionally substituted with halo; R³ is H or methyl; and R⁴ isH or fluoro; or a pharmaceutically acceptable salt thereof.
 2. Themethod of claim 1, wherein the compound of Formula II is a compound ofFormula (I):

wherein R^(a) is C₁₋₆alkyl optionally substituted with one or more R^(b)substituents; C₂₋₆alkenyl; C₂₋₆alkynyl; halo; —C(O)R^(c); —NR^(d)R^(e);—C(O)NR^(d)R^(e); —C(S)NR^(d)R^(e); —C(═N—OH)—C₁₋₄alkyl; SO₂C₁₋₄alkyl;cyano; C₃₋₆cycloalkyl optionally substituted with one or more R^(f)substituents; or a phenyl, monocyclic heteroaryl, or heterocycloalkylring, each ring optionally substituted with one or more R^(g)substituents; wherein each R^(b) substituent is independently selectedfrom the group consisting of —OH, —C₁₋₄alkoxy, —NR^(d)R^(e),—C(O)NR^(d)R^(e), —SC₁₋₄alkyl, —SO₂C₁₋₄alkyl, cyano, halo, andmonocyclic heteroaryl; R^(c) is C₁₋₄alkyl, —C₁₋₄haloalkyl,C₃₋₆cycloalkyl, or a monocyclic, carbon-linked heterocycloalkyl; R^(d)is H or C₁₋₄alkyl; R^(e) is H; C₁₋₄alkyl optionally substituted with—CN, —CF₃, —OH, or a monocyclic heterocycloalkyl; C₃₋₆cycloalkyl; —OH;or —OC₁₋₄alkoxy; or R^(d) and R^(e) taken together with the nitrogen towhich they are attached form a heterocycloalkyl, optionally substitutedwith C₁₋₄alkyl or OH; each R^(f) substituent is independently selectedfrom the group consisting of: C₁₋₄alkyl optionally substituted with —OH,cyano, or C₁₋₄alkoxy; C₁₋₄haloalkyl; —CONH₂; and cyano; and each R^(g)substituent is independently selected from the group consisting ofC₁₋₄alkyl, CF₃, halo, —NH₂, —OCH₃, cyano, and —OH; R¹ is selected fromthe group consisting of H, C₁₋₆alkyl, C₁₋₄haloalkyl, and C₃₋₆cycloalkyl;or R^(a) and R¹ taken together with the carbons to which they areattached form a 5- to 7-membered ring, optionally containing an O or NH,and optionally substituted with one or more R^(h) substituents; whereineach R^(h) substituent is independently —C(O)NR^(i)R^(j), cyano, or isC₁₋₄alkyl optionally substituted with —OH, OCH₃, cyano, or—C(O)NR^(i)R^(j); or two R^(h) groups attached to the same carbon andtaken together with the carbon to which they are attached form acarbonyl or a C₃₋₆cycloalkyl; wherein R^(i) and R^(j) are eachindependently H or C₁₋₄alkyl; R² is —R^(m), —OR^(m), or —NR^(m)R^(n);wherein R^(m) is phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl,pyrrolyl, pyrazolyl, triazolyl, imidazolyl, furanyl, oxazolyl,isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, indolyl, indazolyl,quinolinyl, or isoquinolinyl, each optionally substituted with one ormore R^(s) substituents; wherein each R^(s) substituent is independentlyselected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl,C₁₋₄alkoxy, C₁₋₄alkyl-OH, C₁₋₄haloalkoxy, halo, cyano, C₃₋₆cycloalkyl,NHSO₂C₁₋₄alkyl, and —SO₂C—₄alkyl; R^(n) is H, C₁₋₄haloalkyl, orC₁₋₄alkyl optionally substituted with —OH or C₁₋₄alkoxy; or R^(m) andR^(n) taken together with the nitrogen to which they are attached form apyrrolidine or piperidine ring, optionally substituted with C₁₋₄alkyland optionally fused to phenyl, wherein said phenyl is optionallysubstituted with halo; R³ is H or methyl; and R⁴ is H or fluoro; or apharmaceutically acceptable salt thereof.
 3. The method of claim 1,wherein R^(a) is C₁₋₆alkyl optionally substituted with one or more R^(b)substituents.
 4. The method of claim 1, wherein R^(a) is C₁₋₆alkyloptionally substituted with one or two R^(b) substituents.
 5. The methodof claim 1, wherein R^(a) is methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, or isopentyl, each optionallysubstituted with one or more R^(b) substituents.
 6. The method of claim1, wherein each R^(b) is independently —OH, methoxy, ethoxy,—NR^(d)R^(e), —C(O)NR^(d)R^(e), thiomethyl, thioethyl, methanesulfonyl,ethanesulfonyl, cyano, fluoro, chloro, bromo, pyrrolyl, pyrazolyl,imidazolyl, furanyl, thiophenyl, triazolyl, tetrazolyl, oxazolyl, orthiazolyl.
 7. The method of claim 1, wherein each R^(b) is independently—OH, —C(O)NHCH₃, —CF₃, methoxy, ethoxy, fluoro, —C(O)NH₂, —C(O)N(CH₃)₂,—N(CH₃)₂, methanesulfonyl, thiomethyl, cyano, pyrazolyl,6-oxa-1-azaspiro[3.3]heptan-1-yl, azetidinyl, 3-hydroxyazetidinyl,pyrrolidinyl, or hydroxyethylamino.
 8. The method of claim 1, whereinR^(a) is C₁₋₆alkenyl or C₁₋₆alkynyl.
 9. The method of claim 1, whereinR^(a) is ethenyl, isopropenyl, or propynyl.
 10. The method of claim 1,wherein R^(a) is halo.
 11. The method of claim 1, wherein R^(a) isbromo, chloro, fluoro, or iodo.
 12. The method of claim 1, wherein R^(a)is —C(O)R^(c); —NR^(d)R^(e); —C(O)NR^(d)R^(e); C(S)NR^(d)R^(e);—C(═N—OH)—C₁₋₄alkyl; or SO₂C₁₋₄alkyl.
 13. The method of claim 1, whereinR^(e) is methyl, ethyl, propyl, isopropyl, butyl, fluoromethyl,difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl. 14.The method of claim 1 wherein R^(c) is ethyl, cyclopropyl, methyl,oxetanyl, or trifluoromethyl.
 15. The method of claim 1, wherein R^(d)is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl.16. The method of claim 1, wherein R^(e) is H, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, cyanomethyl, trifluoroethyl,hydroxyethyl, 2-hydroxy-1-methylethyl, hydroxypropyl, cyclopropyl,hydroxy, methoxy, or oxetanylmethyl.
 17. The method of claim 1, whereinR^(d) and R^(e) taken together with the nitrogen to which they areattached form azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or6-oxa-1-azaspiro[3.3]heptan-1-yl, each optionally substituted withC₁₋₄alkyl or —OH.
 18. The method of claim 1, wherein R^(a) is cyano. 19.The method of claim 1, wherein R^(a) is C₃₋₆cycloalkyl optionallysubstituted with one or more R^(f) substituents.
 20. The method of claim1, wherein R^(a) is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl,each optionally substituted with one or more R^(f) substituents.
 21. Themethod of claim 1, wherein R^(a) is cyclopropyl, optionally substitutedwith one or more R^(f) substituents.
 22. The method of claim 1, whereineach R^(f) is independently: methyl, ethyl, propyl, or isopropyl, eachoptionally substituted with —OH, cyano, methoxy, or ethoxy;C₁₋₄fluoroalkyl; —CONH₂; or cyano.
 23. The method of claim 1, whereineach R^(f) is independently hydroxymethyl, methyl, cyano,trifluoromethyl, cyanomethyl, methoxymethyl, fluoromethyl,hydroxymethyl, 1-hydroxy-1-methyl-ethyl, or —CONH₂.
 24. The method ofclaim 1, wherein R^(a) is a phenyl, monocyclic heteroaryl, orheterocycloalkyl ring, each ring optionally substituted with one or moreR^(g) substituents.
 25. The method of claim 1, wherein R^(a) is aphenyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl,thiazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, orpyrimidinyl, each optionally substituted with one or more R^(g)substituents.
 26. The method of claim 1, wherein R^(a) is optionallysubstituted with one or two R^(g) substituents.
 27. The method of claim1, wherein each R^(g) is independently methyl, ethyl, propyl, isopropyl,—CF₃, fluoro, chloro, —NH₂, —OCH₃, cyano, or —OH.
 28. The method ofclaim 1, wherein each R^(g) is independently fluoro, methyl, —NH₂, —CF₃,chloro, methoxy, or cyano.
 29. The method of claim 1, wherein R^(a) andR¹ taken together with the carbons to which they are attached form a 5-to 7-membered ring, optionally containing an O or NH, and optionallysubstituted with one or more R^(h) substituents.
 30. The method of claim1, wherein R^(a) and R¹ taken together with the carbons to which theyare attached form cyclopentenyl, cyclohexenyl, dihydrofuranyl,dihydropyranyl, dihydropyrrolyl, or tetrahydropyridine, each optionallysubstituted with one or more R^(h) substituents.
 31. The method of claim1, wherein each R^(h) is independently: methyl, ethyl, or propyl, eachoptionally substituted with hydroxy, cyano, methoxy, or —C(O)N(CH₃)₂;C(O)NR^(i)R^(j); or cyano.
 32. The method of claim 1, wherein each R^(h)is independently hydroxypropyl, hydroxyethyl, hydroxymethyl, methyl,cyano, methoxymethyl, —C(O)NH₂, or CH₂C(O)N(CH₃)₂.
 33. The method ofclaim 1, wherein two R^(h) groups attached to the same carbon are takentogether with the carbon to which they are attached to form cyclopentylor a carbonyl.
 34. The method of claim 1, wherein R¹ is H, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, fluoromethyl, fluoromethyl, trifluoromethyl, fluoroethyl,trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 35.The method of claim 1, wherein R¹ is H, methyl, isopropyl,trifluoromethyl, or cyclopropyl.
 36. The method of claim 1, wherein R²is R^(m).
 37. The method of claim 1, wherein R² is —OR^(m).
 38. Themethod of claim 1, wherein R² is —NR^(m)R^(n).
 39. The method of claim1, wherein R^(m) is phenyl, naphthyl, pyridyl, indazolyl, orisoquinolinyl, each optionally substituted with one or more R^(s)substituents.
 40. The method of claim 1, wherein R^(m) is pyrazolyl,optionally substituted with one or more R^(s) substituents.
 41. Themethod of claim 1, wherein R^(m) is phenyl, optionally substituted withone or more R^(s) substituents.
 42. The method of claim 1, wherein R^(m)is optionally substituted with one or two R^(s) substituents.
 43. Themethod of claim 1, wherein each R^(s) is independently methyl, ethyl,propyl, isopropyl, butyl, fluoromethyl, difluoromethyl, trifluoromethyl,fluoroethyl, trifluoroethyl, methoxy, ethoxy, isopropoxy, hydroxymethyl,hydroxyethyl, trifluoromethoxy, fluoro, chloro, bromo, iodo, cyano,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, NHSO₂C₁₋₂alkyl, or—SO₂C₁₋₂alkyl.
 44. The method of claim 1, wherein each R^(s) isindependently fluoro, chloro, trifluoromethyl, cyano, methyl, methoxy,cyclopropyl, —NHSO₂CH₃, fluoroethyl, ethyl, propyl, difluoromethyl,hydroxymethyl, fluoromethyl, or methanesulfonyl.
 45. The method of claim1, wherein R² is R^(m) and R^(m) is

wherein at least one of X¹, X², and X³ is N, and the other two areindependently N, NR, O, S, or C—R^(r); R^(p) and R^(r) are eachindependently H; C₁₋₄haloalkyl; C₁₋₄alkyl optionally substituted withOH; halo; cyano; or C₃₋₆cycloalkyl; and R^(q) is H or fluoro; or R^(q)and R^(r) taken together with the carbons to which they are attachedform phenyl, optionally substituted with halo.
 46. The method of claim45, wherein X¹ and X² are each N and X³ is C—R^(r).
 47. The method ofclaim 45, wherein X² is N and X¹ and X³ are each independently C—R^(r).48. The method of claim 45, wherein X¹, X², and X³ are each N.
 49. Themethod of claim 45, wherein R^(p) and R^(r) are each independently H,fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl,trifluoroethyl, methyl, ethyl, hydroxymethyl, hydroxyethyl, chloro,cyano, cyclopropyl, cyclobutyl, or cyclopentyl.
 50. The method of claim45, wherein R^(p) is trifluoromethyl, chloro, methyl, hydroxyethyl,cyclopropyl, cyano, difluoromethyl, or ethyl.
 51. The method of claim45, wherein R^(r) is ethyl, trifluoromethyl, methyl, chloro, H,hydroxyethyl, cyclopropyl, or cyano.
 52. The method of claim 45, whereinR^(q) is H or fluoro.
 53. The method of claim 45, wherein R^(q) andR^(r) taken together with the carbons to which they are attached formphenyl, optionally substituted with fluoro.
 54. The method of claim 1,wherein R^(n) is H, fluoromethyl, difluoromethyl, trifluoromethyl,fluoroethyl, difluoroethyl, or trifluoroethyl, or is methyl or ethyloptionally substituted with —OH, methoxy, or ethoxy.
 55. The method ofclaim 1, wherein R^(n) is H, methyl, ethyl, fluoroethyl, difluoroethyl,or trifluoroethyl.
 56. The method of claim 1, wherein R^(m) and R^(n)taken together with the nitrogen to which they are attached formdihydroindole, optionally substituted with methyl or fluoro.
 57. Themethod of claim 1 wherein R³ is H.
 58. The method of claim 1, wherein R³is methyl.
 59. The method of claim 1, wherein R⁴ is H.
 60. The method ofclaim 1, wherein R⁴ is fluoro.
 61. A method of treating a subjectsuffering from or diagnosed with depression or anxiety mediated by NR2Aactivity, comprising administering to the subject in need of suchtreatment an effective amount of a compound selected from:N-(cyanomethyl)-7-((4-fluorophenoxy)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(4-Fluorophenoxymethyl)-N,2-dimethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide;3-[(Azetidin-1-yl)carbonyl]-7-(4-fluorophenoxymethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;N-ethyl-7-(4-fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(4-Fluorophenoxymethyl)-2-methyl-5-oxo-N-(2,2,2-trifluoroethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(3,4-Difluorophenoxymethyl)-N,2-dimethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-7-(4-fluorophenoxymethyl)-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide;7-((4-fluorophenoxy)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-((4-fluorophenoxy)methyl)-N-hydroxy-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(4-Fluorophenoxymethyl)-2-methyl-5-oxo-N-(propan-2-yl)-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(4-Fluorophenoxymethyl)-N-(2-hydroxyethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(4-Fluorophenoxymethyl)-N-(1-hydroxypropan-2-yl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide;7-((4-fluorophenoxy)methyl)-2-methyl-N-(oxetan-3-ylmethyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-((4-fluorophenoxy)methyl)-N-(3-hydroxypropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-cyclopropyl-7-((4-fluorophenoxy)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-((4-fluorophenoxy)methyl)-N-methoxy-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(4-Fluorophenoxymethyl)-N,2-dimethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carbothioamide;7-((4-fluorophenoxy)methyl)-2-methyl-3-propionyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((4-fluorophenoxy)methyl)-3-(1-hydroxypropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-(4-Fluorophenoxymethyl)-3-(1-hydroxyethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;7-(4-Fluorophenoxymethyl)-3-(2-hydroxypropan-2-yl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;3-acetyl-7-((4-fluorophenoxy)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;2-(7-((4-fluorophenoxy)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)-N-methylacetamide;3-Cyclopropanecarbonyl-7-(4-fluorophenoxymethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;7-(4-Fluorophenoxymethyl)-3-[1-(hydroxyimino)ethyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;7-((4-fluorophenoxy)methyl)-2-methyl-3-(oxetane-3-carbonyl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((4-fluorophenoxy)methyl)-2-methyl-3-(2,2,2-trifluoro-1-hydroxyethyl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-(4-Fluorophenoxymethyl)-2-methyl-3-(trifluoroacetyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;2-cyclopropyl-N-ethyl-7-((4-fluorophenoxy)methyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(4-Fluorophenoxymethyl)-N-methyl-5-oxo-2-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide;2-Cyclopropyl-7-(4-fluorophenoxymethyl)-N-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide;N-Ethyl-7-(4-fluorophenoxymethyl)-5-oxo-2-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide;7-((4-fluorophenoxy)methyl)-N-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-7-[[(5-fluoropyridin-2-yl)oxy]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(4-Fluorophenoxymethyl)-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;7-((3-fluorophenoxy)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((4-fluorophenoxy)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-(2,4-Difluorophenoxymethyl)-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;7-(3,4-Difluorophenoxymethyl)-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;7-(4-Chlorophenoxymethyl)-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;7-[[(5-Fluoropyridin-2-yl)oxy]methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-7-((4-(trifluoromethyl)phenoxy)methyl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((4-fluorophenoxy)methyl)-2-methyl-3-(oxazol-2-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((2-fluorophenoxy)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;4-((3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methoxy)benzonitrile;7-((4-fluorophenoxy)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((4-fluorophenoxy)methyl)-2-methyl-3-(1H-pyrazol-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((4-fluorophenoxy)methyl)-2-methyl-3-(4H-1,2,4-triazol-3-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one;3-cyclopropyl-7-[(4-fluorophenoxy)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;cis-2-[7-(4-Fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropane-1-carbonitrile;trans-2-[7-(4-Fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropane-1-carbonitrile;7-(4-Fluorophenoxymethyl)-3-[cis-2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;trans-7-(4-Fluorophenoxymethyl)-2-methyl-3-[2-(trifluoromethyl)cyclopropyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;7-(4-Fluorophenoxymethyl)-2-methyl-3-(2-methylcyclopropyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;trans-2-[2-[7-(4-Fluorophenoxymethyl)-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropyl]acetonitrile;7-(4-Fluorophenoxymethyl)-3-[2-(methoxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;3-(2-(fluoromethyl)cyclopropyl)-7-((4-fluorophenoxy)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;6-fluoro-7-((4-fluorophenoxy)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-(4-Fluorophenoxymethyl)-3-(3-hydroxypropyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;7-(4-Fluorophenoxymethyl)-3-(methoxymethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;7-((4-fluorophenoxy)methyl)-3-(3-hydroxyoxetan-3-yl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-(4-Fluorophenoxymethyl)-3-(4-hydroxybutan-2-yl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;7-(4-Fluorophenoxymethyl)-3-[2-(2-hydroxypropan-2-yl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-pyrimidin-5-yl-thiazolo[3,2-a]pyrimidin-5-one;7-(((4-fluorophenyl)(methyl)amino)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-(((4-fluorophenyl)(2,2,2-trifluoroethyl)amino)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-(((3,4-difluorophenyl)(ethyl)amino)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((ethyl(3-fluorophenyl)amino)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-(((2,2-difluoroethyl)(4-fluorophenyl)amino)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((ethyl(pyridine-2-yl)amino)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-3-(thiazol-2-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-3-(thiophen-2-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one;3-(ethyl((2-methyl-5-oxo-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)amino)benzonitrile;3-(2-aminopyridin-3-yl)-7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((ethyl(pyridine-2-yl)amino)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((4-fluorophenylamino)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one;3-butyl-7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;2-cyclopropyl-7-[(N-ethyl-4-fluoro-anilino)methyl]-3-pyrimidin-5-yl-thiazolo[3,2-a]pyrimidin-5-one;2-ethyl-7-((ethyl(4-fluorophenyl)amino)methyl)-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((ethyl(4-fluorophenyl)amino)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-thiazol-4-yl-thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-(3-pyridyl)thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-phenyl-thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-2,3-dimethyl-thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-3-(5-fluoro-3-pyridyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-3-(2-fluoro-3-pyridyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;3-cyclopropyl-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-pyrazin-2-yl-thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-3-isopropenyl-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-pyridazin-4-yl-thiazolo[3,2-a]pyrimidin-5-one;3-(5-chloro-3-pyridyl)-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-(4-pyridyl)thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-(1-methylpyrazol-4-yl)thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-(1H-pyrazol-4-yl)thiazolo[3,2-a]pyrimidin-5-one;5-[7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]pyridine-3-carbonitrile;7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-[5-(trifluoromethyl)-3-pyridyl]thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-oxazol-2-yl-thiazolo[3,2-a]pyrimidin-5-one;7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-3-(trifluoromethyl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((ethyl(4-fluorophenyl)amino)methyl)-3-(trans-2-(fluoromethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;3-ethyl-7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-3-propyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-[[4-fluoro-N-(2-fluoroethyl)anilino]methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-((ethyl(4-fluorophenyl)amino)methyl)-3-(furan-3-yl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((ethyl(4-fluorophenyl)amino)methyl)-3-(furan-2-yl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((5-fluoro-2-methylindolin-1-yl)methyl)-3-(furan-2-yl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-3-(thiophen-3-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((5-fluoro-2-methylindolin-1-yl)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-3-(4-methylthiazol-2-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-3-(6-oxo-1,6-dihydropyridin-3-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one;3-(6-aminopyridin-3-yl)-7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-3-(prop-1-ynyl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-3-vinyl-5H-thiazolo[3,2-a]pyrimidin-5-one;3-bromo-2-cyclopropyl-7-[(N-ethyl-4-fluoro-anilino)methyl]thiazolo[3,2-a]pyrimidin-5-one;3-(3,5-difluorophenyl)-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-(1-methylpyrazol-3-yl)thiazolo[3,2-a]pyrimidin-5-one;3-(2-amino-4-pyridyl)-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-3-(5-methoxy-3-pyridyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-3-morpholino-5H-thiazolo[3,2-a]pyrimidin-5-one;3-(dimethylamino)-7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-3-(pyrrolidin-1-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-(((3,4-difluorophenyl)(ethyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile;7-((ethyl(3-fluorophenyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile;7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carbonitrile;7-[(N-ethyl-4-fluoro-anilino)methyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3-carbonitrile;7-((5-fluoro-2-methylindolin-1-yl)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile;7-(((3-cyanophenyl)(ethyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile;7-((ethyl(pyridin-2-yl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile;2-methyl-7-((2-methylindolin-1-yl)methyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile;7-(((3,5-difluorophenyl)(ethyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile;6-[(N-ethyl-4-fluoro-anilino)methyl]-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one;2-[(N-ethyl-4-fluoro-anilino)methyl]-6,7,8,9-tetrahydropyrimido[2,1-b][1,3]benzothiazol-4-one;6-[(N-ethyl-4-fluoro-anilino)methyl]-1-(hydroxymethyl)-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one;6-[(N-ethyl-4-fluoro-anilino)methyl]spiro[2,3-dihydrocyclopenta[3,4]thiazolo[1,4-a]pyrimidine-1,1′-cyclopentane]-8-one;6-[(N-ethyl-4-fluoro-anilino)methyl]-2,3-dihydrocyclopenta[3,4]thiazolo[1,4-a]pyrimidine-1,8-dione;6-[(N-ethyl-4-fluoro-anilino)methyl]-1,1-dimethyl-2,3-dihydrocyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one;2-[(N-ethyl-4-fluoro-anilino)methyl]-8,9-dihydro-6H-pyrano[3,4]thiazolo[1,4-a]pyrimidin-4-one;2-[(N-ethyl-4-fluoro-anilino)methyl]-7-methyl-8,9-dihydro-6H-pyrido[3,4]thiazolo[1,4-a]pyrimidin-4-one;6-[(N-ethyl-4-fluoro-anilino)methyl]-8-oxo-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidine-1-carboxamide;6-[(N-ethyl-4-fluoro-anilino)methyl]-8-oxo-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidine-1-carbonitrile;2-[6-[(N-ethyl-4-fluoro-anilino)methyl]-8-oxo-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-1-yl]acetonitrile;6-[(N-ethyl-4-fluoro-anilino)methyl]-1-(2-hydroxyethyl)-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one;2-((ethyl(4-fluorophenyl)amino)methyl)-6-(methoxymethyl)-7,8-dihydrocyclopenta[4,5]thiazolo[3,2-a]pyrimidin-4(6H)-one;2-[6-[(N-ethyl-4-fluoro-anilino)methyl]-8-oxo-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-1-yl]acetamide;3-cyclohexyl-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-3-isopropyl-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;3-cyclopentyl-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-tetrahydropyran-4-yl-thiazolo[3,2-a]pyrimidin-5-one;3-cyclobutyl-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;3-tert-butyl-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;3-acetyl-7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(N-ethyl-4-fluoro-anilino)methyl]-3-(1-hydroxy-1-methyl-ethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-3-(1-hydroxyethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;3-[(dimethylamino)methyl]-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;3-(azetidin-1-ylmethyl)-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-(pyrrolidin-1-ylmethyl)thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-3-[(3-hydroxyazetidin-1-yl)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-(2,2,2-trifluoro-1-hydroxy-ethyl)thiazolo[3,2-a]pyrimidin-5-one;7-((ethyl(4-fluorophenyl)amino)methyl)-3-(hydroxymethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-[[ethyl(4-fluorophenyl)amino]methyl]-3-(methoxymethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;7-[[Ethyl(4-fluorophenyl)amino]methyl]-2-methyl-3-(1H-pyrazol-1-ylmethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-(methylsulfonylmethyl)thiazolo[3,2-a]pyrimidin-5-one;3-(ethoxymethyl)-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;2-[7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]acetonitrile;3-tert-butyl-7-[(N-ethyl-4-fluoro-anilino)methyl]thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-3-(1-hydroxy-1-methyl-ethyl)thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-3-(1-hydroxyethyl)thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-(6-oxa-1-azaspiro[3.3]heptan-1-ylmethyl)thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-3-[(2-hydroxyethylamino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;3-(ethyl((3-(hydroxymethyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)amino)benzonitrile;3-[ethyl-[[3-(methoxymethyl)-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl]methyl]amino]benzonitrile;7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-3-((methylthio)methyl)-5H-thiazolo[3,2-a]pyrimidin-5-one;3-chloro-7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-3-fluoro-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-3-iodo-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;3-chloro-7-[(N-ethyl-4-fluoro-anilino)methyl]thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethylanilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;3-(1,3-dihydroxypropyl)-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-3-(1-fluoro-3-hydroxy-propyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;3-(1,2-dihydroxyethyl)-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-3-(3-hydroxypropyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-((Ethyl(4-fluorophenyl)amino)methyl)-3-(3-methoxypropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((Ethyl(4-fluorophenyl)amino)methyl)-3-(4-hydroxybutyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((Ethyl(4-fluorophenyl)amino)methyl)-3-(2-hydroxyethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-[[Ethyl(4-fluorophenyl)amino]methyl]-3-(2-methoxyethyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;3-(7-[[ethyl(4-fluorophenyl)amino]methyl]-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-3-yl)propanamide;3-[7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]propanenitrile;3-[7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N,N-dimethyl-propanamide;7-[[Ethyl(4-fluorophenyl)amino]methyl]-3-(3-hydroxy-3-methylbutyl)-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;2-[7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarboxamide;7-((5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((3-chloro-5-methyl-1H-pyrazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((5-chloro-3-methyl-1H-pyrazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-7-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((1H-indazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((5-(2-hydroxyethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((3-(2-hydroxyethyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((3-cyclopropyl-4-fluoro-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((5-cyclopropyl-4-fluoro-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-[(5-cyclopropyl-3-methyl-pyrazol-1-yl)methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[(3-cyclopropyl-5-methyl-pyrazol-1-yl)methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[(3,5-dicyclopropylpyrazol-1-yl)methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-6-fluoro-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;1-((3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-5-carbonitrile;7-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-6-fluoro-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;1-[[3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl]methyl]-5-methyl-pyrazole-3-carbonitrile;7-[[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[(6-fluoroindazol-1-yl)methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-isopropyl-thiazolo[3,2-a]pyrimidin-5-one;7-[(3,5-dimethylpyrazol-1-yl)methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[(5-fluoroindazol-1-yl)methyl]-3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one;2-methyl-3-(pyrimidin-5-yl)-7-((5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-5H-thiazolo[3,2-a]pyrimidin-5-one;2-methyl-7-((5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((1H-indazol-1-yl)methyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-N,2-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-N,2-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-N-ethyl-5-oxo-2-(trifluoromethyl)-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-N-ethyl-5-oxo-2-(trifluoromethyl)-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-N-ethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;2-cyclopropyl-7-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-N-ethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;2-cyclopropyl-7-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-N-ethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;2-methyl-5-oxo-7-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile;7-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile;7-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile;3-(1-hydroxyethyl)-2-methyl-7-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-5H-thiazolo[3,2-a]pyrimidin-5-one;3-acetyl-7-((5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;3-acetyl-7-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;3-(2-hydroxypropan-2-yl)-2-methyl-7-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-((5-fluoro-3-methyl-1H-indazol-1-yl)methyl)-3-(1-hydroxyethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-(1-(5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)-3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-(1-(5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)-3-(2-(hydroxymethyl)-1-methylcyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;3-((3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile;3-((6-fluoro-3-(2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile;2-fluoro-3-((3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile;3-(trans-2-(hydroxymethyl)cyclopropyl)-7-(isoquinolin-4-ylmethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-7-(3-(trifluoromethyl)benzyl)-5H-thiazolo[3,2-a]pyrimidin-5-one;3-((3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)-4-methylbenzonitrile;4-fluoro-3-((3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile;3-fluoro-5-((3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile;2-fluoro-5-((3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile;3-[[3-[trans-2-(hydroxymethyl)cyclopropyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl]methyl]-4-methoxy-benzonitrile;3-(2-(hydroxymethyl)cyclopropyl)-2-methyl-7-(4-(trifluoromethyl)benzyl)-5H-thiazolo[3,2-a]pyrimidin-5-one;4-((3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)picolinonitrile;4-cyclopropyl-3-((3-(trans-2-(hydroxymethyl)cyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile;7-(3-cyanobenzyl)-N,2-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(3-cyano-2-fluorobenzyl)-N,2-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(3-chloro-2-fluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-7-(2-fluoro-3-(trifluoromethyl)benzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-7-(2-fluoro-3-methylbenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(2-chloro-5-cyanobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-2-methyl-5-oxo-7-(3-(trifluoromethyl)benzyl)-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(3-cyanobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(3-cyano-2-fluorobenzyl)-2-cyclopropyl-N-ethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(3-cyano-5-fluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(3-cyano-2-fluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(3-chloro-2-fluoro-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;N,2-dimethyl-5-oxo-7-[[3-(trifluoromethyl)phenyl]methyl]thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(3-chlorophenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[2-cyclopropyl-5-(trifluoromethyl)phenyl]methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-2-methyl-5-oxo-7-((6-(trifluoromethyl)pyridine-2-yl)methyl)-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-7-(2-ethyl-4,5-difluorobenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[3-(difluoromethyl)-2-fluoro-phenyl]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-((6-cyanopyridin-2-yl)methyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[3-(difluoromethyl)-2-fluoro-phenyl]methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[2-fluoro-3-(hydroxymethyl)phenyl]methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(3-cyclopropyl-2-fluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(3-cyano-2-fluorobenzyl)-N-ethyl-6-fluoro-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(3-cyano-2-fluorobenzyl)-6-fluoro-N,N-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(3-cyano-2-fluorobenzyl)-N-ethyl-6-fluoro-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;6-fluoro-7-(2-fluoro-3-(trifluoromethyl)benzyl)-N,2-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(5-cyano-2-methylbenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(5-cyano-2-fluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(2-chloro-5-fluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(3-cyano-2-fluorobenzyl)-N-ethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-7-(5-fluoro-2-(trifluoromethyl)benzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-2-methyl-7-(naphthalen-1-ylmethyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-7-(5-fluoro-2-methylbenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(3-cyano-4-fluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-2-methyl-7-((1-methyl-1H-indazol-4-yl)methyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-2-methyl-7-(3-(methylsulfonamido)benzyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(5-cyano-2-(trifluoromethyl)benzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(4-chloro-2-methylbenzyl)-N,2-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(2,5-difluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(3-cyanobenzyl)-2-cyclopropyl-N-ethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-7-(2-fluorobenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(2,3-difluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-7-(3-fluorobenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(3-chloro-4-fluoro-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(2,5-dichlorophenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;N,2-dimethyl-5-oxo-7-[[3-(trifluoromethoxy)phenyl]methyl]thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(5-cyano-2-fluoro-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(3-chloro-5-cyano-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(3-cyclopropylphenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(2,5-difluorophenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(3,4-difluorophenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(2,3-difluorophenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(4-chloro-2-fluoro-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(2,4-dichlorophenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(3-fluoro-4-methyl-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(2-cyclopropyl-4-fluoro-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(5-cyano-2-(2-fluoroethyl)benzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(2-chloro-3-cyanobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-7-(6-ethyl-2,3-difluorobenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(5-cyano-2-ethylbenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(2-cyclopropyl-5-fluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(5-cyano-2-cyclopropylbenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-7-(5-fluoro-2-propylbenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[2-fluoro-3-(fluoromethyl)phenyl]methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-7-(1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-7-(2-fluoro-3-(trifluoromethyl)benzyl)-N,2-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;3-((3-(2-cyanocyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile;3-((3-(2-cyanocyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)-2-fluorobenzonitrile;6-((3-(2-cyanocyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)picolinonitrile;3-((3-(2-cyanocyclopropyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)-4-methoxybenzonitrile;2-methyl-3-(pyrimidin-5-yl)-7-(3-(trifluoromethyl)benzyl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-(2-fluoro-3-(trifluoromethyl)benzyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one;2-fluoro-3-((2-methyl-5-oxo-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile;3-((3-cyclopropyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)-2-fluorobenzonitrile;7-(isoquinolin-4-ylmethyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one;3-((2-methyl-5-oxo-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile;7-(5-fluoro-2-methoxybenzyl)-2-methyl-3-(pyrimidin-5-yl)-5H-thiazolo[3,2-a]pyrimidin-5-one;2-fluoro-3-((3-(furan-2-yl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile;3-bromo-2-methyl-7-(3-(methylsulfonyl)benzyl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-(3-cyano-2-fluorobenzyl)-2-methyl-5-oxo-N-(2,2,2-trifluoroethyl)-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-(cyanomethyl)-7-(2-fluoro-3-(trifluoromethyl)benzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(3-cyanobenzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile;7-(2-fluoro-3-(trifluoromethyl)benzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carbonitrile;10-(4-fluorophenoxymethyl)-3-(hydroxymethyl)-7-thia-1,9-diazatricyclo[6.4.0.0{circumflexover ( )}[2,6]]dodeca-2(6),8,10-trien-12-one;10-(4-Fluorophenoxymethyl)-3-(2-hydroxyethyl)-7-thia-1,9-diazatricyclo[6.4.0.0{circumflexover ( )}[2,6]]dodeca-2(6),8,10-trien-12-one;7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-3-methylsulfonyl-thiazolo[3,2-a]pyrimidin-5-one;3-(hydroxymethyl)-10-[[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-7-thia-1,9-diazatricyclo[6.4.0.0{circumflexover ( )}[2,6]]dodeca-2(6),8,10-trien-12-one;10-{[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-7-thia-1,9-diazatricyclo[6.4.0.0{circumflexover ( )}{2,6}]dodeca-2(6),8,10-trien-12-one;10-{[3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-7-thia-1,9-diazatricyclo[6.4.0.0{circumflexover ( )}{2,6}]dodeca-2(6),8,10-trien-12-one;10-{[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-3,3-dimethyl-7-thia-1,9-diazatricyclo[6.4.0.0{circumflexover ( )}{2,6}]dodeca-2(6),8,10-trien-12-one;10-{[3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-3,3-dimethyl-7-thia-1,9-diazatricyclo[6.4.0.0{circumflexover ( )}{2,6}]dodeca-2(6),8,10-trien-12-one;10-{[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-3,3-dimethyl-7-thia-1,9-diazatricyclo[6.4.0.0{circumflexover ( )}{2,6}]dodeca-2(6),8,10-trien-12-one;3-((3-acetyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)-2-fluorobenzonitrile;7-(2-fluoro-3-(trifluoromethyl)benzyl)-3-(1-hydroxyethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;3-((3-acetyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)methyl)benzonitrile;7-(2-fluoro-3-(trifluoromethyl)benzyl)-3-(hydroxymethyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;7-(2-fluoro-3-(trifluoromethyl)benzyl)-2-methyl-3-((methylamino)methyl)-5H-thiazolo[3,2-a]pyrimidin-5-one;7-[(3-cyclopropyl-2-fluoro-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-2-methyl-5-oxo-7-[(2,3,6-trifluorophenyl)methyl]thiazolo[3,2-a]pyrimidine-3-carboxamide;2-fluoro-3-[(2-methyl-3-oxazol-2-yl-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl)methyl]benzonitrile;7-[(5-cyano-3-cyclopropyl-2-fluoro-phenyl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-7-[(2-fluoro-3-methoxy-phenyl)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(3-cyclopropyl-2-fluoro-phenyl)methyl]-6-fluoro-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;2-[7-[(3-chloro-2-fluoro-phenyl)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-acetamide;7-[(3-chloro-2-fluoro-phenyl)methyl]-N-ethyl-6-fluoro-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(4,5-difluoro-2-methoxy-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;2-fluoro-3-[[2-methyl-3-(2-methylcyclopropyl)-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl]methyl]benzonitrile;2-[7-[(3-cyclopropyl-2-fluoro-phenyl)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-acetamide;N-ethyl-6-fluoro-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[2-chloro-5-(trifluoromethyl)phenyl]methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(3-cyano-2-fluoro-phenyl)methyl]-6-fluoro-2-methyl-5-oxo-N-(2,2,2-trifluoroethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(2-chloro-4,5-difluoro-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[4,5-difluoro-2-(2-fluoroethyl)phenyl]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;2-[7-[[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-acetamide;2-[7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-acetamide;7-[(5-chloro-3-methyl-pyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(3-chloro-5-methyl-pyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(3-chloro-5-cyclopropyl-pyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(5-chloro-3-cyclopropyl-pyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-7-[[4-(trifluoromethyl)thiazol-2-yl]methyl]thiazolo[3,2-a]pyrimidin-5-one;2-[7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-acetamide;N-ethyl-2-methyl-7-[[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-2-methyl-7-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[3-(difluoromethyl)-2-fluoro-phenyl]methyl]-6-fluoro-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[3-(difluoromethyl)-2-fluoro-phenyl]methyl]-N-ethyl-6-fluoro-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-(4-bicyclo[4.2.0]octa-1,3,5-trienylmethyl)-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-7-[[2-fluoro-3-(1-hydroxycyclopropyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-7-[[2-fluoro-3-(1-fluorocyclopropyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-7-[[2-fluoro-3-[1-(fluoromethyl)vinyl]phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(2-ethynyl-4,5-difluoro-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;2-fluoro-3-[[2-methyl-5-oxo-3-[2-(trifluoromethyl)cyclopropyl]thiazolo[3,2-a]pyrimidin-7-yl]methyl]benzonitrile;3-[[3-(2,2-difluorocyclopropyl)-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl]methyl]-2-fluoro-benzonitrile;N-ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(3-cyano-2-fluoro-phenyl)methyl]-N-ethyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[3-(difluoromethyl)-2-fluoro-phenyl]methyl]-N-ethyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-7-[[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-7-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-3-(1H-imidazol-2-yl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[(3-cyano-2-fluoro-5-methyl-phenyl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(3-chloro-2-fluoro-phenyl)methyl]-N-ethyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-N-(2,2,2-trifluoroethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;2-methyl-7-[[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-N-(2,2,2-trifluoroethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N-methyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-N-methyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N-methyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-N-methyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-N-(2,2,2-trifluoroethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-N-(2,2,2-trifluoroethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;2-chloro-N-ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-methyl-7-[[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;N-methyl-7-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-N-methyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(3-chloro-2-fluoro-phenyl)methyl]-N-methyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-N-(2,2,2-trifluoroethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-N-(2,2,2-trifluoroethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;2-methyl-7-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-N-(2,2,2-trifluoroethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;2-chloro-7-[(3-cyano-2-fluoro-phenyl)methyl]-N-ethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(3-cyano-2-fluoro-phenyl)methyl]-N-methyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-2-[7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]acetamide;N,2-dimethyl-5-oxo-7-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]thiazolo[3,2-a]pyrimidine-3-carboxamide;3-[[2-chloro-5-oxo-3-[2-(trifluoromethyl)cyclopropyl]thiazolo[3,2-a]pyrimidin-7-yl]methyl]-2-fluoro-benzonitrile;2-[7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-acetamide;7-[[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;2-[7-[[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-acetamide;2-[7-[[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-acetamide;7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-3-(methylsulfonylmethyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-3-(1H-imidazol-2-ylmethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;N-ethyl-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-7-[(N-ethyl-4-fluoro-anilino)methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;2-fluoro-3-[[3-(2-methylcyclopropyl)-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-7-yl]methyl]benzonitrile;3-[[2-chloro-3-(2-methylcyclopropyl)-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl]methyl]-2-fluoro-benzonitrile;N-ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-isopropyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;6-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one;6-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one;N-ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methoxy-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;6-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-1-(hydroxymethyl)-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one;2-ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-N-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;6-[[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-1-(hydroxymethyl)-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;2-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-acetamide;2-[7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-acetamide;7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-3-(2-hydroxycyclopropyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;2-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile;2-cyano-N-ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-N-isopropyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(1-hydroxy-1-methyl-ethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(1-hydroxy-1-methyl-ethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(1-hydroxyethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(1-hydroxyethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-N-sec-butyl-thiazolo[3,2-a]pyrimidine-3-carboxamide;3-[[3-(azetidin-1-yl)-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl]methyl]-2-fluoro-benzonitrile;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carbonitrile;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carbonitrile;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-cyclopropyl-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-cyclopropyl-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-(2-methylcyclopropyl)thiazolo[3,2-a]pyrimidin-5-one;3-acetyl-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;3-acetyl-7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;2-chloro-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-3-(2-methylcyclopropyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-pyrimidin-5-yl-thiazolo[3,2-a]pyrimidin-5-one;7-[[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[(5-chloro-2-pyridyl)-methyl-amino]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;cis-2-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-2-methoxy-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-2-methoxy-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-2-methoxy-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-2-methoxy-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;2-[7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-(1H-pyrazol-5-yl)thiazolo[3,2-a]pyrimidin-5-one;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-(1H-pyrazol-5-yl)thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-(3-pyridyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-isopropenyl-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;trans-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(5-fluoro-3-pyridyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(5-fluoro-3-pyridyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-propanoyl-thiazolo[3,2-a]pyrimidin-5-one;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-propanoyl-thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-thiazol-2-yl-thiazolo[3,2-a]pyrimidin-5-one;N-ethyl-7-[[(5-fluoro-2-pyridyl)-methyl-amino]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;2-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile;2-[7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile;N-ethyl-7-[[ethyl-(5-fluoro-2-pyridyl)amino]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-7-[[ethyl(2-pyridyl)amino]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;3-(5-chloro-3-pyridyl)-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;3-(5-chloro-3-pyridyl)-7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-thiazol-4-yl-thiazolo[3,2-a]pyrimidin-5-one;7-[[(5-chloro-2-pyridyl)-ethyl-amino]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(5-cyclopropyltriazol-1-yl)methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;trans-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-[2-methylcyclopropyl]thiazolo[3,2-a]pyrimidin-5-one;2-ethoxy-N-ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(2-fluoro-3-pyridyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-oxazol-2-yl-thiazolo[3,2-a]pyrimidin-5-one;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-oxazol-2-yl-thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[(5-chloro-2-pyridyl)-methyl-amino]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[(3,5-dichloropyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-2-(2,2,2-trifluoroethoxy)thiazolo[3,2-a]pyrimidine-3-carboxamide;3-acetyl-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;3-acetyl-7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;3-[(4-chloropyrazol-1-yl)methyl]-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-isopropenyl-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(1H-imidazol-2-yl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-pyrimidin-5-yl-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-pyrimidin-5-yl-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(3-pyridyl)-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-5-oxo-2-(2,2,2-trifluoroethoxy)thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-ethoxy-N-ethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-ethoxy-N-ethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-(2-methylpropanoyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-(2-methylpropanoyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-N-[(1R)-1-methylpropyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-N-[(1S)-1-methylpropyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[(4-chloro-2-pyridyl)-ethyl-amino]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[(5-fluoro-2-pyridyl)-methyl-amino]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(methoxymethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-cyclopropyl-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-(methylsulfonylmethyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-(pyrazol-1-ylmethyl)thiazolo[3,2-a]pyrimidin-5-one;2-[7-[[2-chloro-5-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-cyclobutyl-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-cyclobutyl-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;2-[7-[[(5-chloro-2-pyridyl)-methyl-amino]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile;7-[[ethyl-(5-fluoro-2-pyridyl)amino]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;3-chloro-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;3-chloro-7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;2-[7-[(4,5-difluoro-2-methoxy-phenyl)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile;2-[7-[[ethyl-(5-fluoro-2-pyridyl)amino]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile;7-[[(5-chloro-2-pyridyl)-ethyl-amino]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;5-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]pyridine-3-carbonitrile;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-(2,2,2-trifluoroacetyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(2-methylcyclopropyl)-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(2-methylcyclopropyl)-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-pyrimidin-5-yl-thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-ethyl-3-(3-pyridyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-3-(2,2,2-trifluoro-1-hydroxy-ethyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[(5-bromo-2-pyridyl)-ethyl-amino]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-7-[[ethyl-(5-fluoro-2-pyridyl)amino]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;3-(azetidin-1-yl)-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;cis-2-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile;2-[7-[[5-methoxy-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile;2-[7-[[3-methoxy-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile;3-acetyl-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-ethyl-thiazolo[3,2-a]pyrimidin-5-one;3-acetyl-7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-ethyl-thiazolo[3,2-a]pyrimidin-5-one;2-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-ethyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile;2-[7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-ethyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile;3-bromo-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;3-bromo-7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;3-chloro-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methoxy-thiazolo[3,2-a]pyrimidin-5-one;3-chloro-7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methoxy-thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-methylsulfanyl-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;2-[7-[(N-ethyl-4-fluoro-anilino)methyl]-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-1-(hydroxymethyl)cyclopropanecarbonitrile;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(2-hydroxy-1-methyl-ethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(2-hydroxy-1-methyl-ethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(cyclopropanecarbonyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;3-bromo-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]thiazolo[3,2-a]pyrimidin-5-one;3-bromo-7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]thiazolo[3,2-a]pyrimidin-5-one;7-[(3-amino-5-chloro-pyrazol-1-yl)methyl]-3-bromo-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[(5-amino-3-chloro-pyrazol-1-yl)methyl]-3-bromo-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;2-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]acetonitrile;N-ethyl-7-[[(5-fluoro-2-pyridyl)-methyl-amino]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(3,3-difluoroazetidin-1-yl)-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methoxy-3-(3-pyridyl)thiazolo[3,2-a]pyrimidin-5-one;2-[7-[[5-bromo-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile;3-chloro-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]thiazolo[3,2-a]pyrimidin-5-one;3-chloro-7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]thiazolo[3,2-a]pyrimidin-5-one;2-acetyl-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;2-acetyl-7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-3-(1H-1,2,4-triazol-5-yl)thiazolo[3,2-a]pyrimidin-5-one;2-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile;3-acetyl-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(2,2,2-trifluoroethoxy)-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;3-acetyl-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methoxy-thiazolo[3,2-a]pyrimidin-5-one;3-acetyl-7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methoxy-thiazolo[3,2-a]pyrimidin-5-one;3-bromo-7-[(5-chloro-3-nitro-pyrazol-1-yl)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(1H-pyrazol-5-yl)-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-thiazol-4-yl-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(5-fluoro-3-pyridyl)-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-propanoyl-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;2-[7-[(3,5-dichloropyrazol-1-yl)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile;2-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]propanenitrile;2-[7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]propanenitrile;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(3-fluoroazetidin-1-yl)-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;3-(5-chloro-3-pyridyl)-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;7-[(3,5-dichloropyrazol-1-yl)methyl]-N-ethyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;3-[[3-acetyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-7-yl]methyl]-2-fluoro-benzonitrile;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-(difluoromethyl)-N-ethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-(difluoromethyl)-N-ethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;(Z)-3-[7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]prop-2-enenitrile;(E)-3-[7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]prop-2-enamide;(E)-3-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]prop-2-enenitrile;(Z)-3-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]prop-2-enenitrile;(E)-3-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]prop-2-enamide;N-ethyl-7-[[5-isobutyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;cis-2-[2-chloro-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile;2-[2-chloro-7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile;trans-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;2-[7-[(4-chloro-1-methyl-pyrazol-3-yl)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile;cis-2-[2-methyl-5-oxo-7-[[3-(trifluoromethyl)pyrazol-1-yl]methyl]thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile;cis-2-[7-[[5-bromo-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile;cis-2-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-6-fluoro-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile;2-[2-methyl-7-[[1-methyl-4-(trifluoromethyl)imidazol-2-yl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile;(E)-3-[7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]prop-2-enenitrile;7-[(4-fluorophenoxy)methyl]-3-[[2-hydroxyethyl(methyl)amino]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[(4-fluorophenoxy)methyl]-3-[(2-hydroxyethylamino)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;2-[7-[(4-fluorophenoxy)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N,N-dimethyl-acetamide;7-[(2-cyano-4,5-difluoro-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(2-cyclopropyl-4,5-difluoro-phenyl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;3-[2-(azetidin-1-yl)-2-oxo-ethyl]-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[(4-fluorophenoxy)methyl]-2-methyl-3-(4H-1,2,4-triazol-3-ylmethyl)thiazolo[3,2-a]pyrimidin-5-one;2-[7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-propanamide;3-[7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-propanamide;7-[[5-chloro-2-(trifluoromethyl)phenyl]methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(5-ethyl-1,3-benzoxazol-6-yl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(3-chloropyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(5-chloropyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;2-[7-[(3-cyano-2-fluoro-phenyl)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-acetamide;N-ethyl-7-[[2-fluoro-3-(1-hydroxypropyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(4,5-difluoro-2-oxazol-2-yl-phenyl)methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;2-fluoro-3-[(2-methyl-5-oxo-3-propanoyl-thiazolo[3,2-a]pyrimidin-7-yl)methyl]benzonitrile;7-[[4,5-difluoro-2-(trifluoromethyl)phenyl]methyl]-N,2-dimethyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[2-chloro-5-(trifluoromethyl)phenyl]methyl]-N-ethyl-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[2-chloro-5-(trifluoromethyl)phenyl]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[2-chloro-5-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-N-(2,2,2-trifluoroethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;3-[(2-chloro-3-cyclopropyl-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl)methyl]-2-fluoro-benzonitrile;7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-3-(pyrazol-1-ylmethyl)thiazolo[3,2-a]pyrimidin-5-one;N,2-dimethyl-7-[[3-methyl-4-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;N,2-dimethyl-7-[[5-methyl-4-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;2-fluoro-3-[(8-oxo-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-6-yl)methyl]benzonitrile;7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-3-[hydroxy(thiazol-2-yl)methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;2-fluoro-3-[(3-methyl-8-oxo-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-6-yl)methyl]benzonitrile;2-[7-[(4-fluorophenoxy)methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]-N-methyl-acetamide;2-fluoro-3-[[1-(hydroxymethyl)-8-oxo-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-6-yl]methyl]benzonitrile;7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-N-(2-hydroxy-1-methyl-ethyl)-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;3-[[3-(2,3-dimethylcyclopropyl)-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-7-yl]methyl]-2-fluoro-benzonitrile;6-[[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-1-(hydroxymethyl)-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one;7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)thiazolo[3,2-a]pyrimidin-5-one;N-ethyl-6-fluoro-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(4-fluorophenoxy)methyl]-5-oxo-N-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;N-cyclopentyl-7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(4,5-dichloropyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(3,4-dichloropyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-2-methyl-7-[[methyl(thiazol-2-yl)amino]methyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(4-chloropyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-2-methyl-7-[[methyl-(1-methylpyrazol-4-yl)amino]methyl]-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[(4-fluorophenoxy)methyl]-2-(trifluoromethyl)-3-[2-(trifluoromethyl)cyclopropyl]thiazolo[3,2-a]pyrimidin-5-one;7-[[(3-ethoxy-2-pyridyl)-methyl-amino]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[(3,5-dimethylisoxazol-4-yl)-methyl-amino]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;3-cyclopropyl-7-[(4-fluorophenoxy)methyl]-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;7-[(4-fluorophenoxy)methyl]-3-pyrimidin-5-yl-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;7-[(4-fluorophenoxy)methyl]-3-[2-(hydroxymethyl)cyclopropyl]-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-3-(4-methyl-1,2,4-triazol-3-yl)thiazolo[3,2-a]pyrimidin-5-one;2-fluoro-3-[[5-oxo-2-(trifluoromethyl)-3-[2-(trifluoromethyl)cyclopropyl]thiazolo[3,2-a]pyrimidin-7-yl]methyl]benzonitrile;N-ethyl-7-[[ethyl(4-pyridyl)amino]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-7-[[ethyl(3-pyridyl)amino]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(2-methoxy-3-pyridyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;2-[7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-isopropenyl-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;3-(5-chloro-3-pyridyl)-7-[[(5-chloro-2-pyridyl)-methyl-amino]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(3-pyridyl)-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-5-oxo-2-(2,2,2-trifluoroethoxy)thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[3-chloro-6-(trifluoromethyl)-2-pyridyl]methyl]-2-methyl-3-(2-methylcyclopropyl)thiazolo[3,2-a]pyrimidin-5-one;7-[(5-chloro-2-pyridyl)oxymethyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-ethyl-3-(3-pyridyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-pyrrolidin-1-yl-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;N-ethyl-7-[[(5-methoxy-2-pyridyl)-methyl-amino]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;3-(2-chloro-3-pyridyl)-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;3-(2-chloro-3-pyridyl)-7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(3-pyridyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[3-chloro-5-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(3-pyridyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(3-methoxyazetidin-1-yl)-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(cyclopropylmethyl)-2-methyl-thiazolo[3,2-a]pyrimidin-5-one;5-[7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]pyridine-3-carbonitrile;2-fluoro-3-[[3-[2-methylcyclopropyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-7-yl]methyl]benzonitrile;7-[(3,5-diisopropylpyrazol-1-yl)methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;2-[7-[(4-chloro-2-methyl-pyrazol-3-yl)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile;7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-(2-methylazetidin-1l-yl)-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;cis-2-[7-[(3,5-dichloropyrazol-1-yl)methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile;trans-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-3-[2-(2-hydroxyethyl)cyclopropyl]-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;3-chloro-7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-5-one;cis-5-chloro-1-[[3-[2-methylcyclopropyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-7-yl]methyl]pyrazole-3-carbonitrile;5-chloro-2-[[3-[(2-methylcyclopropyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-7-yl]methyl]pyrazole-3-carbonitrile;7-[[5-ethoxy-3-(trifluoromethyl)pyrazol-1-yl]methyl]-N-ethyl-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide;N-ethyl-7-[[5-isobutyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidine-3-carboxamide;andtrans-2-[2-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]cyclopropyl]acetonitrile;or a pharmaceutically acceptable salt thereof.
 62. A method of treatinga subject suffering from or diagnosed with depression or anxietymediated by NR2A activity, comprising administering to the subject inneed of such treatment an effective amount of7-(4-fluorophenoxymethyl)-3-[2-(hydroxymethyl)cyclopropyl]-2-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one,or a pharmaceutically acceptable salt thereof.
 63. A method of treatinga subject suffering from or diagnosed with depression or anxietymediated by NR2A activity, comprising administering to the subject inneed of such treatment an effective amount of7-((ethyl(4-fluorophenyl)amino)methyl)-3-(2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one,or a pharmaceutically acceptable salt thereof.
 64. A method of treatinga subject suffering from or diagnosed with depression or anxietymediated by NR2A activity, comprising administering to the subject inneed of such treatment an effective amount of6-[(N-ethyl-4-fluoro-anilino)methyl]-2,3-dihydro-1H-cyclopenta[3,4]thiazolo[1,4-a]pyrimidin-8-one,or a pharmaceutically acceptable salt thereof.
 65. A method of treatinga subject suffering from or diagnosed with depression or anxietymediated by NR2A activity, comprising administering to the subject inneed of such treatment an effective amount of3-acetyl-7-((ethyl(4-fluorophenyl)amino)methyl)-2-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one,or a pharmaceutically acceptable salt thereof.
 66. A method of treatinga subject suffering from or diagnosed with depression or anxietymediated by NR2A activity, comprising administering to the subject inneed of such treatment an effective amount ofN-ethyl-7-(2-fluoro-3-(trifluoromethyl)benzyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide,or a pharmaceutically acceptable salt thereof.
 67. A method of treatinga subject suffering from or diagnosed with depression or anxietymediated by NR2A activity, comprising administering to the subject inneed of such treatment an effective amount of7-[[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl]-N-ethyl-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide,or a pharmaceutically acceptable salt thereof.
 68. A method of treatinga subject suffering from or diagnosed with depression or anxietymediated by NR2A activity, comprising administering to the subject inneed of such treatment an effective amount ofN-ethyl-7-[(N-ethyl-4-fluoro-anilino)methyl]-2-methyl-5-oxo-thiazolo[3,2-a]pyrimidine-3-carboxamide,or a pharmaceutically acceptable salt thereof.
 69. A method of treatinga subject suffering from or diagnosed with depression or anxietymediated by NR2A activity, comprising administering to the subject inneed of such treatment an effective amount of2-[7-[[5-chloro-3-(trifluoromethyl)pyrazol-1-yl]methyl]-5-oxo-2-(trifluoromethyl)thiazolo[3,2-a]pyrimidin-3-yl]cyclopropanecarbonitrile,or a pharmaceutically acceptable salt thereof.
 70. A method of treatinga subject suffering from or diagnosed with depression or anxietymediated by NR2A activity, comprising administering to the subject inneed of such treatment an effective amount of7-(3-cyano-2-fluorobenzyl)-N-ethyl-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide,or a pharmaceutically acceptable salt thereof.